Document RpgoMLkJpEekjkBX25nJqZq9X

Lo 3M JVoeaon r8s. aSowenetney February 16,2010 CERTIFIEDMAIL 3 S3eEenviDreonrmsenotnasl,Healthand 5S 0CPeanlT tHrNBiStD SinAgL0020024-203 Zan S= 52 LA0N59E8-Y37]2 Z7 Z13 pr 2 No CBI DEoPcAumEaesntt--PrRoocoesmsi6n4g28CeAntttenr: Section 8(e) O1f2f0i0cePeonfnPsoylllvuatniiona APrveevneunteiNonW.and Toxics, U.S. EPA Washington, DC 20460-0001 Re: ofFTltSuhoCerAoec8fh(feeem)citScouabflssPt,aFnDBtoSic,aklPeRFtiHs8SkE,HNaoQnt-di0c5eP9:F8SO-uS3lf7oo3nna-ltiRepe-isdbualastnesddfalrinopdompCaraormtbeeoicnxhyamlneiitcsat-bibocalsiiensdvmesitnigation transgenic mice Dear Sir or Madam: z 3baMseids fsluubomriotcthienmgitchailssn(otFiCcse),toansdupmpolreemesnptecpirfeivcailoluysousrubJmuilsysi2o8n,s2o0n06sualnfdonJyalnaunadryc8a,r2b0o0x7ylic `dsautbamistutgaglessctoannceerfnfiencgodfatpaergfelnueorraotoecdiabnycsTulNfOonLaatbeo(rPatFoOrSi)esanindLpeeirdfelnu,orNoehtehxearnleasnudlsf.onTahteese =..=. * (PFHS) onbodyweight,food consumption, and serum cholesterol in 15% dietary fat fed E32 Leiden transgenic mice. 3 Ecunrcrleonstesdtuisdya wfiansalcroepnodrutcfotreafdtolTlNowOuLpabionvreasttoirgiaetsioinn tLoeitdheena,fNoertehmeernltainodnsedussitnugdyA.PTOhEe*3LiedenhuCETP transgenic mice. Results hlp to explain the mechanism ofaction by which apenrifmlaulosrtorbeuattaendeswuiltfhontahteese(cPhFeBmSi)c,alsP.FHSA,n aenffdecPtFnOoSteadltnertlhiipsidstaunddy ltihpaotphraotseninomebeteanboclliesarmlyin demonstrated in other studies on thse chemicals was a decrease in high density lipoprotein (HDL) in animals treated with PFOS and PFHS. Ifyou have any questions, djlucbker@mmm.com. please contact Deanna Luebker at (651) 737-1374 or Sincerely, Geer 3 durnsgf(BX) JViacne BP.reSswideeenntey Environmental, Health and Safety Operations Enclosure . \ CONTAINS NO CB! 324917) nz 003 chaoate51SE ist pt solninAcE CET ice Repro tyence MPFeHcShvanaisPmFoOfSt)hoen epfifedctaonddpiofperreonttsiPnFAmSe'tsa(b9olFiBsSmvein APOE"3-Leiden/huCETP transgenic mice TMpSeiomtaBininoynasmcriiseen,icoe$s)a cc Loen ESneemin Asdueeseis oes: BpeonsaHGnprnscsetn tn ssn: , We eras ofc umber: 021 12685 sway mamos: naan one: 17 Nvarer 2009 tPEeLrn boctr [A -- CONFIDENTIAL SSgrauIrs snTd ate ween Ri IraeSmnEssSe noanom"master rornnsnce Sr ee to er catstry er, in rnteen E tors tees 0S rs cots Em Pe. SUB nerer or nection toPuresWhS have 5 Sec Kren parS es S " f-- : p.3 M803 Mechanism of diffrent PFAST'HsOopnropjiedcatnndulmpboeprro0t3e1i.n12m6e8t5abolisminApOE3L-CETP mice. Summary SPIeuenrrrtfffrialoucudoeorurticoentonacisttoieandonneaaslnrukedlycfluAocnlsiaumtnlegphp(orPnoFapOetrSet)sieiassr,ewTifhdueellylyyadfrlieusopsretirnasaebtdedtIonamehpnhuvimiprahoninslm,iecnftioasrlhg-aaenanitdcinmgmeotwlaiebdcoiulflieec,sdawenigrtdahdsasuttrirfooannc.ge WawPfaottreekrresr,ts.reTaoItxnimceontlthoegwiicptarlhessPetFnuOtdSi;esstuhIdonywervtatehsre,afnosdcuucmshonirskedepuyucsttiohonansvehaasvfheuorwtnnhoetrabereleeudncuicdotabitosineornIvneodfseatrhmueomnmgcehocelhxeaspntoeisrseomdl aPTteFhseSproongasenindbiecPRfaOoprSoB-tochnoenMtoaDbiLsneimrnevgtead(bVoLlcDihLsa,mn.gIeDLTs,heiLnDALPp)lOaEls3pmo-ap.Lreolttrdeiiegnnhsy(cEae3rniLdd)et/soUCainEnvdTe?stcihtgoralatenesstgeterhnoeilceflmfeeovcuetlssoefimnPoFdBteShl,e wDialsoguisceald etfofecsttsubdeyttwheeesne ePfFfeSct,s.PFTHhSe aanidm PoFfOtSheansdtutdoypuIsblfiusthhtehresteo deatmap.hasize the diferences in TpMhearetieorsdituaodlfy,a4nwdwheimecekhtshwooansdsasuWbedisvtiedrend tiynpethrdeiet e(xcpoenrtiamiennitnsg, 1h4ad%thbeeeffoltlalolwoiwn,g 1des%ignc:oraftoelr, a0.r2u5n-i%n PEnBolSes(t3e1r.o8), (3.1 may mbmoait/cykeowrebeiocgedhiytv/eWddealyag)hWtoe/rsdta3ey5)r,3n p0to.ysp0te0i6dvi%eetcPo(FncHtorSnotl(o6l0.).0o0mr3%aa fjweensobftoiedbrrynatwteeylp(ge3h1td./i1edtamyco)o/,nkt0ga.i0nb0ion3dgy%0w.e0PiF3gOh%St. Jraiyg)y.cerIindesailweerxepemreiamseunrtesdbaofdteyr 3wewigahetk,soffootdreaItnmteankte., plasma cholesterol, HDL cholesterol and SaIftnteereroxlps5earwniedmeekfnastttoy1falctiirpdoesl.ayttimAcetnattchteaivneidtnydfo(efLcPetLshewaenerdxepHecLroilamlceetcnitvteidt(y6)fowrweateshkesmdeoeaftsteurrremeaitdnmaetfnirtoo)nm VopLfoDsLbt-it-lrhieagpclaiyrdcisen,ripndleuatasrnmadal eCedaxernpneenuroiimvameoteaensdtu3rape2nodBd.atdpDuerirroridenu4cgcttyw4ieo5hneemkreiswanafuosttfeersmtterhbeaeiasltuImrnfeelvnoditwv,oaabtncildletaahrpreyiandcechneodclooefsmotpfVeorLstoihDlet,LiopeknhxeopseotprfihigomVyleLicnpeOtirLdistdwheaeasn-sdgracldbhleiltpebearlsrmaaitdlndieeeodrsu.twwpaauIsstn. hethteiesrIemnxipvnieevrdoi.mcelInnetaerlxainpvceeerrsiomwfeenartueto3c,loolngleeoxcuttsedtloaabpnelldaedsamHapaOrALtpowwAaaLss maenadsCurEeTd used for aacfttievrit4y waenedkmsaosfstrdeetaetrmmeinnta.tiFornos,m Iver histology analysis, a part was. used or ver pid analysis and 3 part was used for microarray analysks. idPMnaRectBcraSheafarsrneeodidmusccmtelhodeefaprapalhcnaytcsseiimooaolnfocoghVifocLlaPeDlsFLteBe-xrSTpoleraainnmddenVttrLsiDglLIynCcdeiErciaadteendltehmvateildtyhbayrdaeebdcouruceteads2e5VsL%DiLna:nlpdipai4rdt5lc%ee,velprsreosadpureccettiicvoaenul.ys.ePdFTBhbSey hihnaaddHDnnLoo emcfelfeteaacrbetofolfniescAmtL,oTnIannHidDnLed-ecwvhioetllheostpthmeeernoutlncoahfnadhnegapepadtooAsHLtOelLaevtelolessv.esl.sP.FBPSFBsShomwiedldynIoncerfefaseecdontligveernweesigihntv,olbvuetd aBansdeidveornsAizNe iAncrseiagsneadl)s. PTFhBeS parpepseeanrtsdtaotahaivndeicmaitledtPhPatARPsF-BaSgohnaistinco aIcntcirveitayse(dB-CoVxiDdartiiskonpriofniclre.eased MdPaeFtcaShafrnreoidmuscmetodhfepalcpahtsyismoiaonlocohfgoilPceaFsltHereSoxlpearnidmetnrtisglysceurpipdoerlteevdelsbybyheapbaotuitc 6m0R%NAandle7ve5l%s, irnedsipceactteivetlhya.t Tthhee. aaecnctdriveiasttsyreoIsnngpillnyapsrimeadd,ultceheveedlshVeapLraDetiLccTaMGusAeNadnAdbsyiVgLinDnaLcl-rpfeaoarrsteLidPcLllei(o4lp.r3y-os1ds0ulcadtn)idownac.lseIaInnrcarlneicaneseoedfw.iVtLhDLt-heTGhiagnhderVLlDiLpo-lCyEti,c oRPnHNdSAHsOtsLriognnmgaalltysurwdaeetcircoeonansc(elAduBdCHeaDtLt,-hcahtLoClAFeTsH)t.SerTorhleed(suaecbeosaudtHveO-rL7s5el%e)cvehlaasnndgbeyaspdooaArwLen-rm(eaogbsuotluatltii7koe5lny%o)tfhealepvroeelAssul.ltsByaonfstehPdeXsoRin-s 2TTgeeossnptioesntdscibIanecthiefvpoiarttyo.tshtIaenactfrooesraimssae,tdiaorsnemoobodfseelrliavrneggder(bPyLHTbD?lL)ocaphneadmritcdcaeelcsr.aenaPdsFehHdiSsutopiltnoagckireceaal(sSemRde-aBis1vu)errearsweeisguhgtg,estAeLTd,toanbde 2 pd 3803 Mechanismofdiferent PTFNOAopnrSojpei'cdtasnndumlbpeorpr0t3e1i.n1m2e6t5abolisminApoE3L-CETPmice iBnacsreedaseod,n FMARNuAptaskiegnailnscrePaFsHedS, hlaisverstsriozneg inPcPrAeRaas-eda)gonainsdtcPX(Rl-paogloysniisstcincarcetaisveitdy, (BF-Aoxiudpattaikoen iinnccrreeaasseedd),. FA synthesis increased and HDL synthesis and maturation decreased, iver size 6Me5c%haanndis7m0o%f,arcetspieocntoivfePlyF.OAS:simPiFaOrSmreecdhuacendispmloafsamcatichoonleisstearcotlivaenwditthriPglFyOcSeriadse wlietvehlsPFbHyS.abTohuet VdinaLtlDaiLpfiTdrGolmevapenhldyssViaLorleDoLgciapcauarslteiedcxlpbeeyrpiirmnoecdnrutecsatsiseoudnp.plopIornltyelsdiinsebyawnihdtehpcalttehiaecrmahniRcgNehAeorflelVvieLploDlsyLtiTincSdi,accaattenvdttyhsttirnotnhpgellaydsermcaer,deuacsteehdse hsyenptahteiscizmiRngNAensziygmneasfaorndLPcLho(l2e.s1t-e0rlld)estweorsifiicnactrieoansgeedn.ePs.FOMSorIenocvreera,setdhemgReNnAe cloedveilnsgfoofrtchhoelesmtaejroolr `reaxtcer-eltiimointiwneg reendzeycmreeaIsnedthbey bPilFeOSac.idInhsiybnitthieotniocfpchaotlhewsaty,roalnmdetgaebnoelsiisnmvoalnvdedexicnrebtiiloanirmy acyholfeosrtmeraonl explanation fo increased hepatic cholesterol levels found with PFS. MPFRONSAsstirgonnagllsy wdeecrceoansceldudHeDLt-hcathoPleFsOtSerorled(uacbeosutHO-L65l%e)velasndbyapdooAwnL-r(eagbuoluatti-o8n0%o)f l3epvoelAsl. Bsyanstehdesoins aPnOdSHOInLcrmeaatsuerdatiivoenr. wTelhgehste, aAdLvTe,rasnedcrheasnugletsedairnepmroonsoulnickeeldy htehpeatroesstuelattoofsiPsXaRnadgoInviesrticcholaecstteir.ol accumulation, as observed by biochemical and histological measures. Binacsreedaseodn, Increased, MFFAAANusApytnatskhieegsniaIslnscirnePcaFrsOeeaSds,edhlaiasvnerdstsHriozDneLg InsPcyPrnAetRahGse-esadig)sonaiansntddicPmXa(Rtl-uiaprogalotynisiiossntcidnecacrcertaeisaveisdtey,d,(fF-AI.ovxeiurdpattsaiikoznee Increased, Ilinpvooplrvoteemienntmetoafbooltihsemr bnyucPlFeHaSratnrdanPsFcrOiSption factors In the regulation of lipid and IannvdolPvFeOmSenctanonfotCAbRe afunldlyLeXxRcliundetdh,e bcuhtanIsgelsessinIkleilyd. aLnidtelipisopkrontoewinambeotuatbtohleisrmolecaoufsCedARbyInPFpHiSd. Tmheteabloaltitesrm.geCnAeRs hwaesreb,eehnowsehvoewr,n tIoncdreecarseeadseInB-tohxeidparteisoenntgeenxepsearsimeCnPtTs1. aXndRenionyclreCaoseAshyfdatrtaytaasec.d aSXcytRnitvhiietnsydiwuscaebssyfeioxunnpddur.cetsiIsotinocnaonfonfSoRtCEEbTSePPecxmcRelNxuApdr,eedswsthihoeanr,etahwsihsiIscnhctwhaeuassperd2e-sb0eyindt desetxcrproeenrgailsmyeednd,teschroaewaesdveeedcrr.aecaIcsneepatidnodriCtpiEooonTl, hfLoeXrtRe.CrEHoodtwiraemnevsretretr,.ogdIierntevhcoetrlavwceitmtiehvnattioolfnaRrogfXeRrRXinRnu,tmhfbeoerorIbnsoseftranvnueccdeleewafifrtehcttrbsaenxcsaacrnroinptotetinobenelfeeaxaccdtslourtsdoeIdo,ipepsoisPniPctAeeReRGf,XfRePcfXtoRsrmwaisntdah Increased levelsoftriglycerides and apoB-containing lipoproteins MFeencohfiabnriatsem respectively. orfeadcutceidonopflfaesnmaoficbhrolaetseterol and The data from the physiological etxrpieglryicmeernidtes lseuvpeplosrtbeyd baybohuetpat4i0c%MAaNnAd l7e0ve%l,s iOnfdVicLaDtLe-tThGatatnhdeVdLeOcLr-eCaEs,esdeInspliptedtlheeveilsncarreaescedauVsLedOLb-yTGstprornogdluyctIinocnreraastee,d IlnipoilnyesiswiahndtchleeaNriagnhceer p2lp5aarlmaydatarixckieacrcatlifyvoirtiynIcnircneraepsalesasesdmVaLu,OptLtah-keTeGheoppfraoVtdiLucDcLtMiRroNnemAdneassniptigtnpeaarrfteoidrculcLeiPsnLgw(ap4s.l6ae-s(nmohlaagn)TcGwe,adswbhIiyncch1r.e5ma-saefydo,d.beLFDecLnaRoufsimebRdraNbtAye emendhiaantceeddlihpeoplyastiiscoffrVeLeDLfaottrybyacIindcrueapsteadkedernesouvlotihnegpaftriocmTGstsryonntghlaystsa.ccelerated. peripheral LPL. reFfeefsnepocoftnisbirobanlteeapifonoArcLr.te_haeseFIdenncHoOrfLeicabshreoadlteeHstDsetLrroolnlegvle(yl+s5du0ep%cor)neaastnerdeafitonmremCnaEttTiwoPintahocftfilevainrtogyfe,ibHrwDahtLie-c1hanpdWaarPstPiAfeRo,Guyna-dnadgomhnaaijdosrsnl.yo Fcheonloefsitberraotlecionncterneta,sed iver weight, without effects on ALT and hepatosteatost, and decreased Iver uBpatsaekdeoinncrmeRasNeAd, sBi-gonxaildsatfieonnofiinbcrraetaesehda;sHsDtLrornegmoPdPeAlRian-gagdoencirsetaisceda)ctivity (Ipalysis increased, FA 3 p.5 3M803 Mechanismofdifferent PFA"ST'NsOopnrIopjeicdtannudmlbpoeprro0t3e1i.n1m2e6t8a5bolismInAPOE3L-CETPmice contents 21 Tost SUDSKANCES &Ffarance SUBSHANCE 23 Animalwelfare. w1..m. ar--------------------D 2265 27 TCTrooemanptyomuvennetdoghardomcuipnrisstura.ts..i..o.cn rsspnmnm-- ser-------------- ---------- ----------r------------------------------e------3l g]l 221598 2110 MeMMaEesBauSsUurTreEemMmeEenNntttssS eeExxXppPeeOrrHiiMmmEeeNnnEtt 3 r 21..r 1.L.r ..e . ---- --18 311 SEANSHICA] BSI r 16 3 Deviations from the BROOCH uv 7 4.3 R4E1SU1RSMSaErUkBeYrsL of GOo NWGEIrr LBaEINlG..r . i s e 1nl8l SG11123 FM5 LBiOlvaeYsrmaWandELpGT.e..erc iagofaetnWetalm gmdhteal ---- ve-- ennsmm--------`a118 S431176 418 PpPPllaLasosmmSaatArHchiDoglLleyIsctCeerHroiOldIeGs.S.I.lB.I.e.O..s.s ......r .e ..... -- rrH r -- A --`2 S431150 PLliapsoproteBinEpGrIYoCfBIiG rrr w-- --g SS111112 4S111183 FPVPILOoBOsLSBt-MhteUrpiMrgaherSyiecr ne{LrOPitdyLesa8na6dn.dH.e Ld.eBnoGvoIApe .oB.pr.oducr tion ........... 230 ------r3ni8l 42 RP4E2E.SE1USSo MUaErkYerZsoorr f Generalb wellBing-- ...-- anmis---- r--em-- | 33P22E15E4 P7A I0O8SDIANaLKTE crsrr 3256 Plasmacholesterol nn-------- ma------------r CIs47 4G32321875 110 LPPiIlplBaoaSsprImryGaotUHeiDienIL-pccrGihdoosflI,eess.VhtaesrGtaoEroGl aEndRph.osphsolsipnir mdsmp--rn r odun cr tion nm.e.--.t1Sd5O2 442311 BIin'vivobdea arocfaVLnDcL ike TG-rich particies and uptake in tssuss. 57 a ps 3203 Mechanismofdifferent PFTASN'sOopnrojpeicdtannudmlbieporpr0o3t1ei.n12m6e8t5abolism inAPOE3L-CETPmice 43 R4E3S1US SMaArkYerDsoofrgrenweelrlbaonlg CII meniee 4433:23 BLoivdeyr waenldghta.r.i.o.n.adalfatEWrEgImG--h--L--..--.--.--.--.--..-----------r--rr--r--r--r--ry6r5 S43365 FPOlOaIsNmBKaEA.L.oTr.v. ----dl 543.1367 PPIlGaSsINmEaCHOOOGSLRE-IDCIR1.OIESIETDL rrr 668 44.3338 PLlipaospmraotteriingplryofceesr.ides... ------v------------ ------ ----, gy 4433.1110 PPllaassmmaa CAEpTOPRLmL assL . nanen----y7 45331123 PlInaVsImVOa CCETEPacBtiovrfi3tUyaL.I.0N.900cSHDeL... eva--------------7 54331135. LLiivveerrmlpiid canarlysoisD.sGAoTmOGaAMRlY vr. en--------A. 4533.1176 LLiOveEr mNSiRcOrIoOa0rYray anav lysis.r .. s---------- 82 5 CONCIUSIONS aNdCOMMENES vss89 AApDpEenNdGiI1xXL TBIoSdSyUSWWIeGSI...ght e----_g er `AAAppDppPeeEnnNdddiiixxX VIIVI FPOlGaGsmIaNOcKhEolestera.... Plasma HDL-CHOIGSKGrDl ---------- 7106 ``AAppDeDnEdNidxViVIxII PPIlOaSsMmarfQreIeYgClayrcierGoels..............n. n------e--n_-- `AADpDpEeNnGdiiXxVIIXLL PPIOSlMafAarDeOeAsfL.atmyracairds AppendiXx PlCaETPsmamssa... ven--------------------d.lgs rm--------1 0 A`AppppeennddiXiXxIIxL ADPENXGIX PPlosatsmhaepCaErTiPnaLcPtLivaintdy HL SH a--Y--. ----.--. ---- i1i6 Fecal IIS cov ------------y AAppppeennddiixx XXIVV `Appendix XVI BViLlDaLr-yribllyeGaecriidds,eschaonldesdteeronlovaondAppohBosPprOoIdPuIcCtsi.o.n........... 112236 In vivo clearanceof VLDLlike TG-rih particles and uptake in ver... 130 ``AAppppeennddiixx XXVVIIIII ILnivveirvmoicclreoasroamnacleoDfGaAuTtoalcotigvoiuys..HOL A --------E -------- - AJ ApDpDeEnNdGiIxXXXIXX LLiIvVeEr mDiIcArSoarray anaoiysiss..E ........... Le 142 5 p.7 3M#03 Mechanismofdiferent PRAST'HsOonproljiedctannumlbieporpr0o3t1ei.n12m6e8t5abolism in ApOE3L-CETP mice `Sponsor of the study S33tmM.,PCaMeuenld,tiecMrai,lnBnDueieslpodatirangt5m05e21n24t04--0120-00-02 Usa Study contact 3MCJeooMdrhipnCcoearLn.latteBDerue,tpSecaBinruehltnodtmfiie,snntgtPh0.D2.,20C-I0H2-,:D0A2BT FPUStahs.xoaP:naeu:l, ++M11i.n66n55e11s7.o3t7a333..151719746342-.1c0o0m0 Ema: fbitenhoff@mmm Testing facility TDWeaNlli,vaedBrduyrseiasdnsde:rsesPsUs.n:0i.tZ8eoBrxiio2ks2ce1id5ern,ece2els303,1 2C3E33LeCidKenLeiden he Netherlands Responsible personnel Study director POrh.onHea:ns+3M1.G7,1Pr5i1n6ce1n471 EFamxa:il:431ha7n1s 5p1ri8nc1e9n0@1tno.nl Technica staff ASMnianmreoamnnaerBiDerekokMoeagrasBs.B5.8cS.cS.c. MKEaalrrsinieeTPoVesottse8kr.u5mila.enn8B..55c.. DOrr.. Or. JAHonasrijaavnvaanvnadndeerEnrHk.oHoorenk Or. Patrick Rensen Advisors EPromt.a:Dr.loLuousishaMv.ekHeasv@etkneos.nl Eorm.aipla:tripc.kc.Rne.nrseennsenlume.nl s [x] 3203 Mechanismofdiferent PEATSNOopnrpojedctannudmIbpeorpr0o3t1e.i1n2m6e8t5a.bolism inApoE3L-CETPmice 1 Introduction & aim sPuerrffalcueor-itneantseidonalrkeydlucsiunigphpornopaetretsiesa.reThfuelyly aurreisntaabtleedtoaemnpvhiirpohnimlecntoarlgaannidc mmeotlaebcoulliecsdweigtrhadasttiroonn.g waPfaettreefrrlsut.orreoTaootxcimtcaeonnletosguwiiicftaohlnaSPttFeuOdS(i;PesFOhiSon)werivastesrw,iadnesdluycmhdoinrsekpdeeuyrcssteidohnaisvnehhasuvhmeoanwnsno,tafbireseehdn-uccaottibiosnnegrivwneiddsiefaremu,omnagnchdoelsxeusprtofesarecodel wtorraknesrgse.nicInmooursdee,r taowoebltraeincomgonriezeIdnsaignhitmanltomotdheelpfososihbylpeermleicphiadenmiisamaonfdaactthieornostchleerAoPsOisE,*3h-aLsebiedeenn duisfeedreIntacphraeivniloeunsgtsht,udPyFBtoS i(nCv4e)s,tiPgFatHeS t(hCe6)InavnidvoPeFfOfSect(sC8o)f,Cohn rplpaesrmfaluiordo-salaknydi-sliuploppnroontaetienss waintdh b3inlMdeusiatncrtiihdaelmaebptepaglbiionclnaiitsnimgo.nosfOf20t0h0e tbehcraeusPeFoAfS,enPvFiHrSonamnedntPalFOISsshueasv,ewbheeerneawsitPhFdErSaw'ns mfarrokmettheedmianrvkaertiobuys. AicnoPnOcfEoi*nn3terLdaestitodettnohe twVriaLdnD-sUtgy/epLneiDcLmmsiiiczceee,d eAlxPihpOiobEpi*rt3otLeeeliienvdaeftrneacdttirpoalnnas(sg1me)an.iEcchxotmleiencssetievraeorle.prahenivdgihotlurysigrrleeycsseepraoirndcsehivlseevhetolosw,efdmatatiahnnald,y cc3h)h.oylleoIsmntiecrarodlodnifteiaeondndi,ngVwLaeDsLfhaarpvraeosdutfchoteuinoednffeatcnhtdas/toorndrptulhgeasshmaeanpaVdtLiOdcLiectalanerdayrcahncycoelmopmoofiucrnloidnpsoplreiovntfeelliuneasnrceeixncegornteciertrehlneaertdivte(hl2ey,. csotnrtornagste,ffienctnsoromnal pwlialsdm-atypcehomleiscteertohle apnldastmraigclhyocleersitdeerollevaelnsd (almost) not responsitvoe diet and hypolpidemic drugs. (t4r-ig1l1y,cesriedee floervelrsevaireew vererf.y l1o2w). anIdn Tlfhpbiorspartaoentsiemieantlc)lmeovd(e4el:,l8,hlai1sp0o)pbreoaetnnedipnrnopuvrtorefinitliteoosn,b(ei9t,srepr1r1e)es.speonnItnsaitvaidevdneietsfiosorn,ttohedhehypupeomnldaiinpnigsdietmouinactitodhnreurgelsgevaer(ldIkieon.fg spptllaaatssimmnaa, cinholheustmearnolsAPwiOtEh*3rLeesipdeectn mtiocecadlelvuealropcoamtphoesroistciloenrotaincdlemsoiropnshoilnotghiecaaloratnadreismemmbulnionngistthoocsheemfiocuanld TchNaOracItnecraisltaibcosra(3t)i.on with the Leiden University Medical Center has recently developed the APOE3- omLfeetladdberonulg(isEc3Las)ny/dnMdUrCnouEtmTrePi.ttiroInananlstghefenacitncoermwsoluyosneg,enpwelhraiasctmheadhaHmsDopLursoeav,nednhtutomribagenhyvcceehrroiyldeessutileteravobelllse,efsotaretrhteersttorisancnglseftrehoresipesrfofteaecnitdns (r2epNs0UuBCl-EtciTonPng)tianuinnadiemnrgorcloeinpthorupomrloaotnfe-ilniistskeinnalteiupxrocaphlraoftnlegaiennkifpnorgrofrtreiiggiwloiyncteshriitdsreasi.nnstfrAeosrduoacfecrdhesoIulloetstotrfhoetlhAiePssOtEae*drSv3fe.rr-osLmeeidHlieOpnLopmtroooutteshieen dttirrsaatnnrssiggbeeunntiiicco.nmmiaicncede (1dt3eh)ve.elhoipgheIrncraemaosuedntatohferaostchleerroogseinsiconapaoBW-ecosnttearinntiyngpelidpioptro3t5eincso,mptahered3,to.CEETSPL Tst0haehtiunEmsaSn(L1sC5,E),TwPintihatcrdiaenncs(rg1ee6an)siectshmeiniCctEehTePraepIsonphBoi-bncidotnottroationtrircneegtartpampoeipnbrto(tw7e)iitahnts(sarinemdgiilsaatrnedrieondsc)aregdaersseugansndHaOsinLfailbesvreailtsel.sa(1w4a)y, FhtrarevoaemtestdthreAoPpnOrgEe*cv3hio-olLuesesitsdetreuondlymaiInncdeAPtaOrliEsgo*l3ys-cheLroeiwideedsednltothwreearnfisongrgemnaeitfcfieocmntisc.oef,Laiitp"owlpaarrsogteceioHnnDcLplr"uodfpeiaderstthioaeft,PPpFFrHHeSSsuaamnnaddblPPyFFOOaSnS ainpcorEe,asecdholpelsatsemryal AeLstAeTr-rliecvhelsHDaLn-d1 lpivaerrtiscc.e,Modreecorveears,edPFbHilSe aacnidd PsFyOntShetsriesataenddancihmolaelsstesrndlo-w7ead- chInhycedrmreioacxsayelld.aseePneaFrctSgiyvidetiyxf,pfeeIrnnedcdirtmeuaarsreekdevdifalatybtyufrrancoiimndgoFoxfHifSdaatt,ainoandi,PsaRunOgdgSedsbetycirnhegaavsPienPdgAbRnaodayogrowneoiinsglthyta,mcitenvpoitrdykeiffoyfrmecattlhsefsoaent tatwnhade thmeeashiugrheedr pdaorsaemaeptpelrise,d washecroemapsarPeFdHStoaPpHpOeSa.red to have Intermediate effects taking Into account oIbnstehrevepdrecsheantngsetsudiy pthleasfmoacutsriigsypcuetriodnesaafnudrtchheorleesltuecriodlateivoenlosf itnhethmeeacthhaenriogsemnircesappoonbs-icbolnetfaoirmitnhge `(mVeLtDaLb,ol1is0mL., TLhOeLr)efolriep,opirnottehiinsssatunddy ttoheimnvoersetigaaptperoptrhieateeffAecPtOoEf*P3G-SL,eiPdFeSn(aEnCSdELTP)?F/GStraonnsgeHnOiLc. 7 po 3M#03 Mechanismofdiferent PRTASH'sOopnropjiecdtannumlbpeorpr0o3t1a.n12m6e8t5abolism in AOE3LCETP mice emfofuecstes bmeotdweelenwaPsFBuSs,edP.FTHhSeaanidmoPFfOtSheansdtutodypusblfsurhtthehresteo deamtap.hasize the diferences In biological 11 Alm of the study T3aonddelPcuhRcoOildSeasttaeenrtdohletolmeeIvnecvlhesastniniigstamthoee ftahtaehceterifoofgneecnrieocsfpaoPpnFosBBiS-l,ceoPnfFtoraHiStnhiaenngodb(sPVeFLrODvLSe,doIncDhLHa,nOgLLeOsLm)eItnlaipbplooalpsiromstameitInrnsigEbl3yyLc.ePrCFiEdHTeSPs tarnadnstgoepnuibclimsihcet.heTsoe edmaptah.asize the differences in biological effects between PFBS, PFHS and PFOS 5 p.10 M803 Mechanism ofdiferent PETASN'sOopnropjekctaundmbIpeorpr0o3te1i.n2m6e8t5abolism in ApoE3L-CETP mice 2 Materials and methods 21 Test substances & reference substance Test substances: Reference substance: PPFFSS ((ppeerrffuloorroobhuetxaanneessuullffoonnaattee)):: L1-277043986,-l8o0t,2l(ot19L999O)S1 PFeFnOoSfi(bpreartef:luFor6o0o2c0t,anleostu1l1f7onKa1t4e8)6:.FC-95, lot 217 PFeBnSof,ibPraFtHeSwaansdpuPrFcOhSasewderferopmroSviigdmead (bSyt. 3LMousM,edUiScAal).Department (sent to TNO on 10-Jun-04). 22 Mice hBaavseed uosnetdhemlaalreges diifnfertehnece pinrohpaolsfeIdfe ebxeptewreiemnenmtasl.esO(n1e7-hh)unadnrdedf-etmwaelensty(3hm)alIen CDh-e1termoizcy,dowues A(LPeOiEd*e3nL)ehiadveenCbeTePn umsiecde,, a7n-d10houwseeedksduorfinagget,hefreoxmpetrhiemeSnPtFInbrmeaecdrionlgonstcocakgeast (TmNaO-xBilmoasc4lemniccees pTeermpecraagteu),re I~n2_1clCe,ang-chotnvceynctlieon7aalmatnoim7alpm)r.ooImnsdivaitduaTlNOan-iLmeaildsenare(rmelaartikvee.d bhyuemairdtpyunc5h0--na6l0e%s, Mice were supplied with food and acidified tap water ad Ibitum. 23 Animal welfare ELxopweroinmAennitmsawleErxepepreirmfeonrtms.edEcxopnefroirmmetnotsthheadrubleeesnanadpprreogvueladtiboynsthseetAnfiomrawlarEdxpbeyrtihmeenNtetChoemrmlaintdtsee oinf TcaNsOe uofndseerrioreugsisutnreaxtipoenctneudmbaenirma2l48d3i.scTohmfeorstt.udy director was entiied o terminate experiments 24 Diets Maincde0r.e2c5e9i%veodfWcehsotleerstnertay)p,e dpiuertc(hWasTeDd; fsreommi AsyBnltehtestic(Wdieertdceonn,taiTnhiengNe1t4h%erlbaendes)t.allTohwi,s1r%esucloterdiiln tDoiteatlscwhearleestreernoelw(eTdC)onpcleapsemrawleeevekl.s of about 8 mmol/L and triglyceride levels of about 2 mmol/L. 2.5 Compound administration TFehneofriebqruaitreed(qSuiagnmtai,tieSs.ofLoPuiFsS),aPsFHSusaenddaPsFaOSpowseirtievesucpopnltireodl.byAll3Mco(mspenotuntodsTNwOereonad1m0i-nJiusnt-e0r4e)d. aorcaclolrydiansgatod: iOpteoratthieonWTDp.rocPerdeupraeratniuomnboefrall14dioefs "(Lwaibthordaitfoerrieunmt pcroomcpeoduurnedss.)Uwpeirdeenp"erefnotrimieedd "VParceupaurmatbiaognsoifn adnieltacrhmu-nskescufrreodm-2p0owCderroeodm.food". The Iyophiized diet chunks were stored in s [0 3M#03 Mechanismofdiferent PETASN'sOopnropjedctanndumpboeprro0t3e1i.n2m6e8t5abolism in ApOE3LCETP mice 26 Treatment groups. GGGrrrooouuuppp 12:: 3: WWTIDD WTD d++ie00t..0033 9%% fPeFnBoSfib(rwa/twe) (owr/w3)1.o1r% 3m1g./8%kgmab/okdyg wbeoldgyhtw/edlagyht/day (positive control) (G=G"rrAoovuueppr45a::geWWTTIDDnta++ke00..o00f0063co%5mpPPoFFuHOnSSds((ww//bwwa))seoodrr 63o..n01%7ammvegar//akkggge bbbooodddyyywweewileggihhgtth//tddaaayynd food Intake in the three Indicated experiments 27 study design Design experiment 1 Weoefvekatmesnt: |A A2101112134516] [G(rGoruopu12p::dWeTtDWT+0D.03% fenofibrate (Group 3: WTD +0.03 % PFBS. x A m ----xmx=mt b mt mimmimmmimmmmmen ([GGrroouupp45:: WWTTDD ++00..000063 %%PPFFOHSS. X Kbxxmm mem--e--m--e | | [Bodywent andiood intake | a EE (A-- = [bSSeaPcrrgiofincaedaElFDTEadAiE-popsle asmLas,rsuseeerrum,e iver, 4 Experiment 1 was performed according to the scheme as outlined above. IAtwnyeprrseehuoirdrtina:etnpd(eocrmoiinoztdeaidonfion4ngwb1eo4edky5swwbeeiaegshftst,taalprltloewad,smw1ait%chha5cl4eosrtmeaarlisle),,0E.HS2DL5L.-Cc%EhToPlchemosliteceserteorloonla).nadsItnermiwgelsyeycknetrh0iedtetsihce(waaefnseitrmeadrlnns FpWalesartseinmgaM)ecIahnso5luergsetrdeoruoaplt,s o1Hf-O08Lcawhneoielmkeassltseaarnnadd,4tthraeing6ldy-cweereiwdkeesse,ktrsgelaytctemrreonltsawtnaadts fsortfeaerttrefedaat.ttmyBeonadtc.yidWsPeli(gaafhsttme,ar(40Ah0LdAfTIansttaaisknega,) pT2aad0ri,aomace4it,ievri6tyf)orwewveaeksrscdol(alAmeLacAtgTee)d aannddlitpodp,rote6in at 6 weeks for wpmereoefakissluesr(ewpmeoerpnertomsteeaoifsnuprlepardsomfneas)pl.oeovelleEsdxtosrfaamtphpelleacssompmaeprogu(rwniodtushpobuaytt 3m ApPfletatesrrmaa5 wsftereeorkmolssfaoasftnetddrefmaaitcymeena(tci4dnlsp.ofayAstttiicntgha)ectaeinvniddtyfoef(cLetPshLewaeanxsdpecHroLlilmaeeccnttitevdiVtLfyDo)rLwtathrseigmdleeytcaeesrruimrdieendaatnifdornodmoefponbsoitvlhoeapacaiprdiso,n ppfrrlooazdseunmct,iiosnleqruwuiadmsnaimntedraosgpueenrrieagdnodnaasndtadolrpeaidddibpeoclsooemwpto-sssi7ut0eioCna.ndofIVveLrDLwawsascoldleetcetredm.ineBdo.th AtfitsesruessacwriefriecediErDecTtAl-y The run-in periodofstudy 1 started on 25 March 2008, mice were sacrificed on 6 June 2005. 10 p.12 3203 Mechanism ofdiferent PFAST'NsOopnrpojedctannudmIbpeorpr0ot3e1l1n2m6e8t5abolism in ApoE3L-CETPmice Design experiment 2 Weoefvekamesnt [G[rGoruopup12:: dWeTtDwT+D0.03% fenofibrate [[GGrroouupp34:: WWTTDO ++ 00..00306%% FPFBHSS [Group 5:WTD + 0.003 % PFOS [232A 01121314] xX ------xb x mommmo x ngxm ---- | Xxt mimme] (Bl conoustion(Bt tow,QELEL biesat] rm [pSeacrrgifoinceadElDTaAd-ipploassemtai,sssueerum, er, El Experiment 2 was performed according to the scheme as outined above. IAnrsuhno-ritn: period of 4 weeks was started with 38 male E3LCET? mice on a semi synthetic western twyepreedriaetnd(ocmoinztaeidnionng b1o4d%y wbeiegehtt,alplloaw,sm1a%chocloesmteorio,l,0.HD2L5-c3h%oclheaslteesrtoelrola)n.d Itnriwgelyeckeri0detshe(aafnemral4sh fpalswatesiemnkgas).cIhnoPlSleasgstemrraoolA,uLopAHfDTsL6-acashnoailmepasaltsrearamonledtaetnrhdefto4rr-iwgIlevyeeckresrdidtaermseaa(gtaemteenartnd4whalsifpaosspttarironttgee)di.nweBproredoyfmeewsaesiwguahrste,dmfeaoatosdtu=ir0netdaakneId,n ppoloalsemda s(awmipthloeustpreardigoracotuipviatty)tw=a0sacnodll4ecwteedekats 4(AwLeAeTk)safnodr tm=e4aswuereekmsen(tIspopofroptleiansmparolfeveesl)s.oEfxttrhae compounds by 3M. AdDfiutrreeircntgl4y4w5heemreiekansfuttoeefrsttbrhieeeatIfnmleovnwi,tvobaitlciltaerhyaercahenoncldeestooeffrotVlLh,DeLp-ehIxoipskeperhiotlmrieipngiltdysctehraeinddegsa-blrlliecbhlsaapdtaderoruttewpsautswwaceasrnenduemlteaeatrsemudirneeaddn.,d ApRereirgosnaacdraiflicaediEpDosTeAptlisassumea,andseirveurmwaenrde dpierreictgloynafdraolzeandIinpousiedtinssiuteroagenndalnidverstworaesd cboelleoctwed-.70ThC.e "eTxhterarumni-cien fperroimodsotfudsytu3d,yus2esdtafrortebdiloenca1n6nuJluanteio2n00w8e,remiscaceriwfeirceedsoancri2fiOccetdoboenr1250A0u8g.ust 2008. The n p.13 3203 Mechanism of diffrent PFAS"'TsNOopnropjiedcatnndumlbpeorpr0t3e1l.n12m6e8t5abolism in ApoE3L-CETP mice Design experiment 3 Weoef ekatmsent [G[rGoruopu1p2:: WdeTtDwT+ 0.03 % fenafiate [G[rGoruopup43:: WWTTDD ++ 00.0.3 %%0PPF0FBHS6S.. [Group 5: WTD + 0.003% PFOS [A] 3] ZITO]1121314] N xe --t -- fx emme XXx x mm Xx mm m mm (Besrveiitand2ioodinake a ra roy e------------ (pSeacrrgiofincaedEaDTsdAi-popsleasmtai.sssueerum, Iver, inteste, L[a ivmerRNAhiiss-- toollaotgiyon -- Iver, mi-- croara-- yTver-- [ LrL ep ,er ments of 5 ed = =% Experiment 3 was performed accordingtothe scheme as outined above. wtAIynerprseehuodrrnitae:tndp(eocrmoiinoztdaeoidfnion4ng wb1eo4ecky9s%wbweeaiegsfhtst,taalprltloewad,smw1ait%chcha3ol8rsntmearolsi)e,,0E.H3O2LL5.5-CcEhToPlcheomsliteecsreteorloonla)n.adsItnerimwgelsyeycknert0ihdeettsihce(waaefnstitemea4rlhns f(paalsfatesirnmga)4hcIhnofla5esgsttirneogru)opl,swoaHfsD7mLeacanhsioumlarelesstdearaontldtat=nh0de a4tn-rdiwgel4eykcweserietdkreses.aiaAmneLdnAtTplwaaasssmaastpaAraptroeadA.mle,tBeoCrdEyTfo?wreaiicgvtheitrv,itdfyaomoadandgIenmtaaaksnesd, wmlieepeaoksprsuortee(ilmniepnoptprrosofitolefcisnplwpaarssomfiameesl)ae.sveulrEsoextdfraitnhpeplocaooslmemdapos(uaWnmidptslheobusytp3erMra.dGirooaucptiaitty=) 0waasndco4llweecetekds a(tAL4AT)weaenkds tfeodr HWCAotaDlesLlrewicats3ecsdadwtfeeeretdokemasrnmtdihofenreatrddreiteoiranlota-m5boeermnlbietidcaleownivpeeteihrnm,*ogHruA-ocsuhpepoalreotfsofrotfee2raty4chlhehlriegvayrfe!otrueperwtahaWesnra.sdiinTrjseheaccecttrliiyIofnnifcvroeiofdvzoe*bnHcy-licehCaolOrli;aeqnsuitcadeenrndyoilftsraooeulgerteyounl.lmoegtHwohaOuesLsr. 2dlanlbdpeolsestdeortaeiudstsobuleeolgoaownuds-7l0HivDeLrC.wfoeArreeMrAcoNslAaeccrtiisefodil.cateiTonhE.eDTTAsh-maeplllIaVsIemnrat,ewsatissneecruuwtmaIsnafdniodruercstpmlaayrltlfsr;oizntetwneostiipnnaerl,tlsqopuedritnghioetnraoIdgvaeelnr taWnheaerleyissidosilr,aetciotonlnyeofpfraormztiecnwraoIssnomluiesqseu.idd fPnieixrreidoggoiennnabduaaflnfdeardseitdporofesodermtbaiesilsnouwefo~wra7Is0vedriCrehcfitoslrtyoMlfoRogNyzeAannIdsionalaqtpuiaoirndtawnnaidtsrIouvgseerendpaifnoddr Stared below 70 C, ONG mouse per group was used for an extra bie cannulation at t=5 week. eTExhxcepeeprrutinm-teihnnetpfeexortirosadtoufmdiysct2eu,dwfyerro3emsstsaatcrurtdiefydico3e.nd oT2nh8e2JsueOlcymti2oc0be0e,8r,2u0ms0ie8cd.e awsereextsraacrmfiicceed foonr 2t5heSebipetecmabnenrul2a0t0i8o,n 2 p14 M203 Mechanismofdiferent PETAHOoSnpr'pojsdectannudlmpboeprr0t3e1i.n12m68e5 taibnoABolE3iL-sCEmTP mice aTnhaelysliasstwamesapseurrfeomremendt in(CweEeTk a3c8t,iv2i0t0y9).was performed on 7 September 2009. Liver histology 28 Measurements experiment 1 21)) PBloadsymaweichgohltesatnedroflo,odHOiLntackheol(epsetrercoalg,e)traitgh,ce4ridaensd, 6glwyeceekrso.l and free fatty acids (after dh Pfalsatsinmga)cahtol0e,stearonlda6ndweterkigsl.ycerides were determined using kit "Cholesterol CHOD-PAP" and dKiette"Trrmiignleydceurisdiensg G"tPhOe-fPrAePe"glbyactehroflrdoemteRromcihneati(oMnanKnch"erimo,mGSeirgmmaany()S.. PLloauissm,aUgSlAy)c.erPollawsamas HfrOeLe-cfhaotltyesatceirdoslwwearse ddeetteerrmmiinneedd uussiinngg kkiitt ""CNhEoFleAsCte*roflroCmHOWDA-KPOAP(*Nefursosm, RGoecrmhaeny()M.annPhleaismm,a 3) G(Up5eo0rp0mra1onUty/e)mibna)t.perroftehse partegcirpoiutpatiloenvelofaatp4oancdont6aiwneienkgs.pdUpsopbryotMenlCnls,w(e0r.2e msoelp/aLr)ataenddbhyepFaPrLiCn aSnaamlpylseiss upseirnggroaunp.AKCThaAleasptpearroaltuasn.d ApnhaolsypsheolsipwiedreprpoefrefsorwmeerdeImnefarseushrleydoibntatihneedfrapcotoiioends "uPshionsgphoKliitpid"sC"hoflreosmteIronlsruCcHheOmDi-ePA(Pe*lzf,rotmhe RNeotchheerlan(dMsa)n,nhreesipme,ctivGeleyr.many) and kit 4) PspleacstmraopAhLoAtTomaettigcroauspsalyoevfelthote0R,oc4heanRdef6lotwreoenksp.lusPlsayssmtaemA(LMAaTnnwhaesimm,eaGseurrmaendy)u.sing the 5) aLinpdoprhoetpeaitnicliplaispeasaendachteipviattyi)c pwaassedaectteivrimtiynaetd5awseedkess.crLiibpeodlytpireavctiiovuistlyy(i(p1o8p).roteIinn slhioparste:. Pafotsetrheipnatrrianpepriltaosnmeaalfrionjmecftaisotnedofmihceepa(r4ihn) w(0o.s5 c1ol0l/e9ctbedodfyromweitghhet).talPvoesitnheaptar2i0n mpilnaustmeas tNraiCalcyltgolyecsertoilmahtyedrbooltahsethaectilviiptoyprwoatesindeltieparsmein(eLdPLi)n atnhde pherpeasteinccelpoarseabs(HeLn)ceacotfiv1y.maiLlP.L 6) aVcLtDivLirtiygwyacsercialdceulaatnedd VaLsDtLh-eappoorBtiopnroodfucottiaonpaansdelaicptiidvictoymIpnohsiibtiitoedn boyf 1namsocle/nLtNVaCLlD.L at 6 Cweoemkpso.sitTihoen roaftenoafscheepnattiVcLVDLLOLw-tarsigdyectereirdmeinperdoduIncti4on,hrde(onrovooveranpiogdhts)ecfraesttieodn amnidcelip3id dmeisdcarziobleodmprIenvtiroaupselyri(t1o8n,ea1l9).anIdn Isnhjoretc:tedMiicnetrwaevreneouasnleysthweitthize0d.1wimtih fplhuoansipshoantee--fbeunftfaenryeld. b3saopldoiyBnewsceyonlntgthhea)sii,nsi.wnghAif1ct0he0rviC3rt0IuamTlilrnya,ncTMotsmh-pellaaebtneeillmya(lIIsnChNriebBciietoiemvdeeVddiLcaDaLlTsrc,tloeInarvriWannRec,1e3Ub3Sy9A)blInotjcoekcmitneigaonsLuP(rL5e0m0eddemiaan/tokevgdo Iapnodlypsil.asmBalotcidgshaymceprldeesswceornecednrtarwanti0o,ns15w,er3e0,m6e0asaunrded5.0Amfinra9f0termTirniuttoensWmRi1c3e3w9erInejekcitlieodn adentderm"bilnoaotdiownaso'f dceolineocvteod apbyoB hseyanrtthespiusncatniodnVLfoDrL csoomlpaotsiiotniono.f VFLorDLthaatndpurspuobsseeqVuLeOnLt pGalrrtaiccelnetsri(fduegantsiiotny. <Th1e.0p1r9o)tewlnerceonsteepnatraotfedthefrVoLmDLothferarctliiopnopwraosteidnestebrymidneendsitbyy g3raLdoiwernyt dpreotteerimnindeedteursmiinngatKiiotn",ChoalnedstertorliglCyHceOrDi-dePsAPa"ndandtoKtiatl "Tcihgolyecsetreirodles cGoPncOe-nPtrAaPtiboonsth wferroem Rdeotcehremi(nMeadnunshienigm,kitG"ePrhmoasnpyho)l.ipiPdhso"spahnoldipKiidt "Farnede cfhraeleesctheorloelstCeroblotchonfcreonmtrIantsitornuschweemriee (pcruDerecvilepfitf,iatttiTiohnnge o(NftertaehpneodriBlnaenwsdist)wh.iihTshopterhoe*p%aeSnq-ouala.pt0io8Tnh:ceonVptLleDansLtm-aoTfGTVGpL=rDaoLd*utwcitamiseonm+eraatsb,eurwIenadswahcfiatclehrculsaealtieescdttibhvyee `CAaplcouBlaatneddepxrpordeuscstieodnarsatyem).olL/ipdipdmcoAmppooBs.ition ofVLDL was calculated per newly synthesized 7) 4FFee8cc:aa7ll2belhxetcaicmriedesp,toefrnibieiooudtlnreaIlnac3sitdessr,uolbnsgerauotnurdaplsfasatttteyr2oalccsiodansnsewdceufrtaeittvdyeeattceiirmdmesinapetodintinwsefdeeukcnessng(cno=lwlee6ectkpeed5r,dgubrryoiunGpg)a&.s 8) AcEfhDtrTeoArm-aspaticoragisrfmiacapeh(iaatcls6(oGwCne)eeeakdnseald(yesfniodsr aIossfoVldaLetOsicLortniorbifegVdyLcpeDrerLviidaoenusdalnysdu(b1Vs9L,eDqL2u0-e)an.pt08deptreordmuicntaitoinonexopfedreimneonvto) i2psplsaousBemsawynaatsnhdewsesiisegrahunemdd awVenLrdDeLdiccrooelmcltpelocystieftdrioorzneo)n,mIsnheuerauirmtd,pnupinetcrrtioiggooennn.adaTanhldeasdltiiovpreoresdaebntedslsopuweer-ia7gn0odnaCld.iavler.adEiDpToAs.e 3 p15 3M203 Mechanismof diffrent PFA"ST'NsOopnrojpeicdtannudmlbpeorpr0t3e1i.n12m685etainbAPOoE3lL-CiETPsmimce 9) Plelvaeslsmaoftcakoemnpoautnd6s.weSeakmsplaefstewre4rhe sfeansttiongn wdrays cseenbtytFoed3eMx cfoorurimeerasonurDeemceenmtbserof1p%l2a0sm0a8 and arrived at the 3H center on December 22008. 29 Measurementsexperiment 2 12)) pBPlloaadssymmwaaeccihhgoohllteessattneerdroolfl,oaoHdnOdILnttrciahgkalelye(cseptreeirrdoeclsagawene)dreattrdi0eltyaecnredmrii4dneewsdee(kuasst.ienrg 4khitf"aCshtoilnegs)tearto0l aCnHdOD4-wPeAePk"s.and KcGhteorlme"saTtnreiyrg)ohlcaefwrtaeirsdetshdeeGtpePrrOemc-iiPpnAietPda"tiuosbnionotgfh3Kpif0tr8o"mCchoonRltoeacsitnheiernogl(lMpCadHnsOnDhbe-yiPmAM,Pn*CGlferr(0om.ma2nyRm)oo.c/hLe)Pl(aaMnsadmnahnehpeHaiOrmLi,-n 3) (Luis5pi0on0pgr1oaUtnjemiAbn)K,pTAroafppiaraattugsr.ouApnlaelvyesleast4werweeepkesr,fLoirpmoepdroitneifnrseswhleyreobsteapianreadtepdooblyedFPsLaCmpalneaslypsiesr CgIhrnoosultper.sutcehCrehomollleesCt(HeDOreoDll-fPa,AnPdt*hepfhrNooesmtphheRorlolicaphniedds)(pMrraeonsfpneehcsetiiwmvee,lryeG.ermmeaansyur)edandin Kitthe"Pfhroascpthiaonlsipudssi"ngfrKoimt 4) 5) psBplleaecstmcraaonpnAhuLolAtaTtoimoaentr,igcrboaiusepsafylleoovwfe,lthabetiaR0roycahnedcRhoe4lfelswotetererodknls,.plupPshloasssypmhsaotleiAmpLi(dAMsT,anwnbahiseeimma,ecaiGsdesurrmeaadtny)u4.siwnegektsh.e Dpreetveiromuisnlayti(o2n0).ofIn bsiholratr:y TIhIepicd_osmecmroetniobnieadnudctobfileanfelsotwhetwiazsed dmeitceermwiansedligaatsed,deasncdritbheed Gfdlelotbwelrawmdaidsneermdewaasususirnecgda.n.nKuClthaotl"eeCdsh.toelBreiosleltewraoanlsd cpohlColHsepOchtDoe-ldiPpIAniPd15caonmndicneunkttiretast"iIPonhntosesrpvihanloslbiiflpoeirdws4e"5remfirdnoeumtteersR.moicnBihelede a((cMMiiadsnsbnehwceekir,me,thdGeeetNreemrtamhinenyrel)danadinnsd)bIinlestursuicnhgemKiiet ("tDoetlazlib,ilTehaeciNdesthaesrslaanyd"s)f,rormespLeucctriovnelyB.ioTportoaldubcitles: 6) VCILlnDesaLhroalrintkc:eeDtoirfrgelVcyLtcDyeLr-aiItdekeser-rbpcaehrtpciaacrnetnsiuclaianstdiwoaunpsetaxadpkaeeprtiInemdeInvfterVroaLmtDwLh4awkteeewkaessm,udleTssihcoerniIbnpeadvritpviroceevcsilocueosnaltyraai(nn1i9ocn)efg 2dWoe0sr0eeCotifak1ternmigoflrtoermiignltyhaceenrditadi2els0vpeCienIr. m"o"*uCHs-ceah.noldeAsLCte2r,yla5c,toil1ve0iat,tiee2s0wweaernredeI3nc0joeucmntitendedb[lnitonood1t0hseapmtlpallseevsreui(nmSOaatunida) CSEoxprtlrreeaeccntteeaddnfdforromtmuosttcahllees.etir(sufsmeuemsvoorblayulmsea).n woAevterrtenheicgeohlntldeicnotcfeudtb.haetAileolxnpteairtsis6mu0eesntCwIeIvrnere5,0hw0eeaiirgth,Seodpl.evraibUglpoeinda(sdPaelwrekaritn,e EpGiaomrseteri,=ebsWeeelwlhae"ssl,ecyia,nlcwUuhSliaAct)hedaanbidsytrhcaeudricvcaealcctufiliavtttieyndgwha(arslenmfdeeiaisonuferstehdew.iltaThbheetlehdeclVeLeaqDruLaantlciieoenr:apta%ertoifoefsV)LI.DnLje-cItkeed 7) Aphfeltaaersrtmps,uacnrcritefimiocaeni.nadtTeh4rewirveeeemrkasainn(ddeenprdeorfoifgtohInneadvvaielvroasdViaLpnDodLsepceltreisiasrguaoen.ncaedEaeOxfTpaAte-rtpiimlseasnustems)awcweoarllseeccdtioirloelncetcoltfyedEfrDfoTrzAoem-n 8) im1ne5alqisuuirodefnm(ientnortonsgreandoifaonpadlctasistvmoear)edlpelvbeaelslsmoawof-t7ca0koemCnp.oautnd4s.weSeakmsplaefserw4erefassetnitngonwaGsryseIncte tboy 3FMedfeoxr Courier on December 1 2008 and arrived at the 3Mcenteron December 2* 2008. 2.10 Measurements experiment 3 12)) BPPolldaayssmmwaaecihgcohhltoelsaetsnetrdeofrldo,lo,HdDLIH-nDctLahk-oeclhe(osplteeersrctoaelgraoenl)datatrnid0g.alnycdterrii4gdwleeyscee(krasif.dtesr 4hwefraestindge)taetrm0iannedd 4 uwseienkgs. Kit "GRCeohrcomhlaeens(tyeM)ra.onlnPhlCeaHismmO,aD-HGPDeLAr-mPcahnoalyne)dstaeKfrittorl"twThraeisgpydrceecetirepdriemtsaitnieGodnPOuo-fsPi3AnpgPo*kBitbco"oCtnhhtoalifenrsiotnemgropRlodCcshHeObDy-(PMHaACnPnl"hef(ir0mo.,m2 3) mLSioiplno/gplr)oatnaeniAdnKhTperAopfaalripiepnsar(aat5t0uGs0r.o1u0Ap/nmaeLlv)ye.sleastw@erweeepkesr,foLripmoepdrIontefirneswhleyreobsteapianreadtepdooblyedFsPaLCmpalneaslypseirs Group. Cholesteral and phospholipid profes were measured in the fractions using kit 1 p.16 3203 Mechanismofdiferent PETANS'OopnropjedctannudmIbpeorpr0o3te1i.n12m6e8t5abolism in ApoE3L-CETP mice "ICnhsotlreusctheermoileC(HDOeDl-fP,APt*hefrNeotmheRrolcanhdes)(,Marensnpheecitimv,elGy.ermany) and kit "Phospholipids" from 4) PspleacstmraopAhLaAtaTmeattrigcraosuspayloevfetlhaetR0ocahnedRe4flwtezeokns.pluPslassymsateAmL(AMTanwnahseimm,eaGseurrmeadny)u.sing the 5) PusliansgmaKitCE"TRPoaarctCiEviTtPy (Ac1t7i)viatnydasmsaasysK(i1t"6)fraotm0Raonadr 4Biwoemeekdsi.caClEITnPc a(cNteiwvyYowrka,s UdSeAt)e.rmCiEnTe?d Jmaapsans).was determined using the CETP ELISA from Daiichi Pure Chemicals Co. (Tokyo, 6) dPferltoaemsrmAmabincAeapdmoAupslii.ngc(oCn2acmesbnartnridadwtgiieco,hnUEKaLt)ISw0Aasa(1nc6do)a.t4edRwaoebvebekirstn.iagnhPttlia-(sm3mogau/semApLAo)pAoloAnltcoopnoCcloeysnctltaorrnaatslitroainpnssti(wbNeoerdwey Y9o0rk,miUnSA)atat347CC."anSdubwsaesquiennctulbya,tedgowaitth adnitluit-emdoumsoeusAeppolAaLsmaan(tidbiotdiyonf1r:o4m00,R0o0c0k)lafnodr I90mmumnionchaetmi37caCl.s IFinnca.ll(yG,ibHeRrPts-vciolnej,ugUaStAe;d driaubtbiotn a1n:t3i,-0g0oa0t) w1a9Gs aadntdiesdodayndfrionmcubRaotcekdlafnodr I90mmmuinnocahtem37icCa.lsHRInPc. w(aGslbdeerttsevcitlelde,bUySIAn;cudbialtuitoinonwi1t:h15t,e0t0r0a)mewtahsylabdendzeiddianned firnocmubOartgeadnfoonr 7) T(IenSkavcnioiv,koaUcS(AlB)owetaes,aoufrTshaeeaudtaoNnseltoachgeosretulasannddHasOr)Ld.a.tpu4rwiefieekds.moTuhseeraAdpiooAlaLbelfirnogmofBiaoudteoslioggnousInHteDmLatainodnaIln tVihveo rcaldeiaorlaanbceelionfgauotfolaougtooulsogHoDuLs wHaDsL,perofnoermmeoduassedefsrcorimbeedacphreveixopuesrliym(e1n4t)a.lIngrsohuoprtwFaosr weuatshacnoilzleecdtebdy Oanyd, dainrdectbllyoofdrowzaesn dirnawllnqufidronmittrhoegernetraon-dorbsitaolrevdeinb.el(oOwne7p0iec<eCoffotrhemRivNeAr IdIsenonclsuaibttaiytoinounain(td3ra7IcveCne,trr2il4uighda)stiwodinet.the*rHHm-iDcnLhaotlieo(sn0t).e.3r2ySleparmluomel wetaHhDseLr-ccolhlaolbleeceltseetddereaognlg)dyoHlwDkaLsphwaarssapdhiIaastioialdabyteeildcedhaafitbneyer vmuelLst)iaccleenfstrro(im4f0ugaECt3iiloen0l..d5FenrmCgtEhToePfipnhmioisvcpeoh.ocllieSpauirbdas)neciqneuoetfnhtealuypt,roelsoHegnDocLuesoHwfDalLsi,pomprireociteseoiwane-trdeeedfiicnaijfeetncettresdedvreiunamstih(t1ey aatil8veaimn. wiBtlhooadtwraacseocfoaluletcotleodgaotus1,"H2-,ch4o,lestaenrydl 2d4eyh eafttheerr ilnajbeeclteidonHaOnLd(0*.H1-aycCtiivny7w8aS)s HcoOuntceldeairnanpcleawsamsa csaalmcpullaetsedtobydectuerrvemifniettitnhgetipmleafsrmaamede0c-a8yho(ftr*eHn-dcihnoelseswtietrhytohleeyelqueatthieorn H9%ouo)f. Injected dose=100%6"TMTM, In Which 3 Is the calculated fractional catabolic rate of 8) pAfltaesrmas,acrsiefricuem,atli4verw,eeskmsall(einndteosftiinne vainvdo MpeOrLigcolneaadraalncaediepxopseeritmisesnute). coElOleTcAt-iopnlaosfmEaOTaAn-d Spaerrtusmanwdasthceolslemcatleldifnrteosmtihneeawrterpeundcitrieocnt.lyTfhreozienvrinwlaiqsuiwdeniigthreodgeannadndcutstionre4d pbaerltos,w t-w7o0 r"Ce.maOinndeerpaorft twhaeslifviexredwaisn Upsheodspthoatiesolbautfefemriecdrofsoormmaelsinfo(r1D0G%A)Tfoarctivveitry mhiesatsoulorgeym.eTnhtes f(preorzeInvIenrlimqiucidronsiotrmoegsenwearned isstoolraetdedb)elPoewri-g7o0nadCa.l adipose tissue was weighed and directly 9) m1e5auslurofem(ennotn-sraodfiopalcatsivmea) lpelvealssmaoftcaokemnpooutnd4s.weSeakmsplafetserw4ehrefassetnitngonwadsryseincte tboy3FMedfeoxr 10) cDoGuAriTe2r oacntiDveitcyeimnbleirver1%mi2c0r0o8soamneds.arTrihveedDaGtAtTheac3tiMvicteynItnerivoenrDmeicceromsboemre2sw2a0s0d8etermined aDsGAdTes2craicvtievditpyreIsviionuhsilbyite(d7,at18h)igIhnerthceonpcreensternacteioonfs 5ofmMmgaCll/L(1o0r01m0m0am/mLo)l,/LDGMAgTC2l,actSiivnictye c(oannlybeDGcAalTcIulaatcteidvibtyy)sfurbtormactthiengDGthAeTDaGctAiTvitayctiinvittyheInprtehseenpcreesoefnc5emomfol10/0L mMmCohl/L(DMGoACTlIy 11) MaincdroDGaArTra2yacatniavliytsyi).s control of the RNA, mliicvreorsa:rrRayNAanawlayssisIswoalastedcarfrrioedm ocuotlleactteSdervliivceer XpiSecBe.s,. A(fLteeirdeqnu,altihtey `Nage)ethneormleanMdOsZ)43u0s:in2g.0thaerraAyfsf.ymDeattriaxwetercehnseonltogtyo TplNaOtoZerimstafnodr gAfefnmeetxrpxreGsseinoenCdhaitpaanmaolyussies 12) gLriovuepr.lipLiidvser(FlCi,dCsE,weTrGe adnedtePrLm)inIend6bsyamapHlPeTsLpCerangarloysuipsaansdplrievveirohuissltyoldoegsycriinb5eds(a2m2p),les per 15 p17 3M203 Mechanismofdiferent PEATS'HsOonplropjiedcatnudmbpeoprr0o3t1e.n12m6e8t5abolism InAPOE3L-CETP mice 211 Statisticalanalysis. fCSiooglmnlpioufwitecdearnbcyepr3oofgMradanimfnf-eSWrPeiSnSfc.neseyAbeUKt-rwtueessektnelflotr-hWeIanlgldsreopuetpnessdtenwtfaosrsasmceapvllecerusal.latAeIdnPd-nevopanel-nupdeeanr<tam0es.ta0rm5ipclwaealss, cwuoasnsisnigduesretedhd,e Statistically significant. The resulting p-values were given In separate tables In the report. 16 p.18 3803 Mechanismofdiferent PFAST'NsOopnropjedctannudmIbpeorpr0o3te1i.n12m6e8t5abolism in ApoE3L-CETP mice 3 Deviations from the protocol Experiment 1 It-nrUjepeacottlmeeydnttcI.ntacrItanipsveitrteiytaoddneetoaeflrlmy1i,n12atU0i-ohmnei:pnaurPtioenss/t-gbheefbpooarderyicnowlpellieacgtshimtoano0w.fa5psoIscUto-lhlheeecpptaaerrdiinin/ngpwlebaeoskdmya5 wIenistgehatd hoefpwaerienk w4aosf 2*FeWccoenesdseeccwuietdrievedenctooiltmlteeoctpceoodilnldteuscrtiofnIgv4e83r h4poi8uerchse.sanfdoahicsotnosleocguytainvaely7s2is,h vtiemre ppedrioadnaIlnys3issuabngdromuRpNsAinisstoelaadtioonf iWandRds-.1s3u3Ibn5steeq(sutuiesnenedtwtmaoiscbrlcooolcalkrercVatLyedDaLnInaclelyxesapirsearnIincmeee)nxtpceo3ruilImdneshntateavd1e obafuntexeipfnfeeercxitpmeeornnitmlei1v.netr 3g,enseinceexpirnejsescitioonn aonfdTrfiitvoenr I~"sAoLltiapitsdiaocncroi(fmvipicaoesuinlttoiroasnceenortfurmiVfLuwgDaaLtsiioscno)el-xiepcrteesds,edonlpyerEdOTpAm-pSla-sAmpa.oBAlilnsotfeatdheofplpaesrmamgwapsrotuesien,d sfionrceVLtOheL. pprroopteerilny.concentration was very low in the PFHS and PROS treatment, and coud not be measured Experiment 2 ec-xatn5rnauelxamttiricaoensmwiecforerefduresotemedrmeisxnipanectreiiomnseonomtfeb3imlie(coefnleofwr,moombuisleeaxrpyepercrihmalegernsottuapr2o)lh,waedprheotsopuhbsoeeldipeixtdcosl,ipdeberidfleofrarmcoimdesx.tarnaaTlhyobsisilese bpbiellcaeacpuersmoeednuotcftoiapoenvreadrtriyaostnli,ocwaalnbldyi.lthperomdiuccetiwone.reThneotewxaclrumdeednamuigche dcuoroilnegd tohfef tboiol cmaulclhectdounr,inwghitchhe acfafnencutleed ui~vpetCralkebeairoiapnntcvseeartofoefvVeLVrDLyLD-Llb-lilokloekdepsparaatrmitcpiliceesnsga3npdatinhutep,teatnokdeomfiItnnihmleiivzeVerLDalLtoscs4loewfaeremakinscce:e. WexeNpeexdrteicmtieodnettd,hetionlsiovtenerla,yduompfteataakskeuirnoegf V-ALtDL-saickreifpiacretnicolessewrausm mweaassucorleldecitnedh,eaorntl,ymEuDsTclAepl(afsemmao.ralN)o,Ipnteersitgionneawafast caonldlescptleedena.nd stored in liquid nitrogen. Experiment 3 `I~mnTosrutesaeetapmdeeornftg0rw.oau4sp uwsMtaasrHtuOesdLedwpieftrohrga5rnoguerpxo,tur0pa.s3b2iolfeJ7cMaanHnniDumlLaatlwisaosnIn(usstseeeeaddafloosfro 5draegdviriooaltuaipbosenlsionfIgn.6eTxahnpieemrarilemsa.esnotTnh2)ef.orextthrias aW-naWdsestduhaebtcsieldqeeusdennttohtamntioc0r.c4oolulaerMcrtaHyeDaLrnawlpayisseicisessIanifteoexdphiefsrrtioommleongttyhea1nPabPluHytsSiisan,nedvxepPerFrOipSmiedtnrtaena3at,lmyiesnnitsceagrnIodnujpmescR.tiNoAn oifsoTlraittioonn iW~ dRAs-ft.1e3r3Inc5toen(sstuuislnteeadtwitaoonsblcwooilctlkhecVtthLeedDLSinpcoelnxesaporearrnic(mese)enetcoe3umlaIdnislhtaecavoderroaefnsepxeopfnfederecintmceoenntofl1iv2ef8ro-rg3taeh1na-et20se0xa9pm)re,esrwseieaosnodnea.cniddeIdvetro sp-eeMlriefccotrreomdsogmmeiencesrsow.earrreayisoalnaatleydsipseronIvtehreInIsvteerasd ionfscteoamdbionfinIgve2r vaenrds;intpeesrtignralouMpA5NrAemaanianldyseirss ooff sIvoemrse. were used for microsomes isolation. rl p19 M803. Mechanismofdiferent PFAST'HsOonplroijedcatnnduImpeorpr0o3t3e.n1m2e6t8abolism inApOESL-CETP mice 4 Results 41 Resultsstudy 1 411 Markers ofgeneralwell-being owutorhuiennrdgsfptrheoecmisftfiucgdlhiytniioncagnl.eAsimngoantushsewerer(memoouausbseseer(2vm2eo)duswdeaursi1n5pg)utsthhienowsaetdusdeysp.aormAaettessacccraaibgfseicneb,etcbhaeeusisbdeeeslaftahareneavo.eprNeson SRoomemwancarotscaonpaircgaddifienrstnhceefsenowfeireb.rataebsGerrovuepdanbdetSwreaennglytheen_agrroguepds.in tLihveerPsPHwSeraendviPsRibOlSy group. 412 Bodyweight VIandliuveisduaalreboadbysowleuitgehtvsaalrueesgi(vgenraimns)apapnedndare|. means + S.0. from 8 mice per Group. [rr f[= Feerrrae EErEasESmTT e TeT o T] T ar3 rasTwa Aw 7 w7] p [o mr r ------ > Teenie|--os7Tose|Looo | 09s | Teo orress TToosseo1T0oammC eT|oo0es7su||oosmos||| C ros | osJ s-- |7 om00|1 7 aO re |Cow0 eco||| pros 1 oss | oss| ooo |ori| auirfifnergentchees swteurdeyoabnseinrcvreedase in ody weight was seen. Between groups no significant srs m---- R--T------ h.orizon = I ge 3% ~e-prOS i3 i bd g30 I . Time (weeks) tt cre------ Ea T o oe] -- I [r EE r CTr i e [Eenoforate10.001 T0234 | ert [eens T<0.001 10.083] [Fenofibrate'vs [r1 es 0.010 0793 8 | pe er aae f frros 1" <e.001T0065 frros 1"<0.001T0130] . p21 3803 Mechanism of diferentPAST'Hs anrepjiedctamnudmpboeprro0t3e3i1n2m6e8t5abolism inApOE3L-CETPmice LiSinhvcoerwreseadsweeadrreeobsruisgtnWiiefniidgcuhaecnsitonebyniarrlegsvepdeecWtinieviaegilhyttr,+e4arte4sm%peenctatingvdreolu+yp1bsy.5%F+e1n6Tofh2ie6brPaatnFedSa+n1ad5n5dPF%P,SFOSwt.hriecgahrtomwueapnsst SS5ek5ea%n,Snpganl0il.ct0ar0en7a)tt.ymehnitghgerrouapss,coomnlpyarPeFdOS10sitghnefiFcEaBnStyoduescr.easAeRdNopuesrhga3nadSiaglhtatdewceriegahste(wa5-s Figure 8.1.38 Liver weight 5 CFeononfitbrate apa 41 acperronss 8253 $52 * RFioo Pail ] . Ee 1 oa weak& + p<0.05 vs. control Figure 41.3 Perigofnatawdeiaghlt 12 4 3s zSos Eos go4 3[X} `aaCFpoornnatorstoilrate PFHS. mprOS . pedi . oEsF 00 week 6 +p<0.05 v. control 2 p22 SHEG3 Mechamofdeen FAp Son idr and prote ein metabolism nApCEoT Emice 414 Foodimake VTarlu:es Paorutaabsst vsaluesa(rBomiomouyse/sdey)reaned nars mesaanpser+e50. fram 3-4 cages per hl]S--TS-- ooToi sa T =e] rSreesE e d== s e Sa S e --% r p aeTea[ee% ] a rm aa [a [romerane pemp emese]1] [Controlvs: FenofibrateT100010.11 0.1 4004| Se om v1.mm com [pres T 1.000T070 1.000 0 | em mm com Fenofibravtes [Pres | 0400 |"oa1a|1.000 | -- rn| fros 1"oes 0400 0.229 | fpros T1000T0700 0.22 | A groups sowed a smr fod ke, Faure 414 Foodintake . 3I S22 3&i, o 10 p<a05 vs. cont = 01 a4 Time (weeks) a ci Tohnrveer rTerre ss p23 Mees MechanismofdierentPA'TsHOonprpojdecannudmIbpeorpr0ot3e1i1n2m6e8t5abolism inApOESLCETP mice 415 Plasma aut (Va8lmuiecseapreragbrsooulput)eatval=u0e,s 4(Uan1d) from measurements o In poled plasma samples per group [ FoF ef s Te odwis[e craeews| ie | AfletshsorugehxtennodsPtaHtiSstiscaelemanaolyisnicsrecaosuedpbaespaerAfLoTrmleevdelso.n pocied ALT levels, PFOS ond to & Figura 415 Plasma ALT 1000 ~=GFoannooftlrate _ 00 p~rpproroisss 2 wo 2 wo 200 ---- o 4 0 1 2Time (3woeks)4 5 68 7 2 poe M803 Mecha ofafr 94'Ss 1nd sneppst?ttl in ASL GET mice 4s Piasma cholesterol Values aeaaebsttevaalruse (AgmsLoannd aaepmepanas & 50. rm 8 ice per ron pre wl Fmr r % dels T a] =aI ]EE - [Ee[0] rr 43 o I EE [pr [ Fm rr ] Ee e m Fenofibravtes [Fenofibrate11.000| 0.001 |<o.001| [1 prs 0.9 <0.005 1| <o9 .001| [res | 0950| 0.028 |006s| [PEs 10:87 | <0.001|<0.001 | [p1 ros 0.17 <o.009 1| 05 .002 | [p1 ros 0."|6 "<o.007 1 |<o6 .001 | ANl sTarRa gerno?upsFsahorwetds2 Sdeaannand oednucsticon hin polasrma S cholesh trol ai14pantds6 SS78oS5m,aBnESoananEOSeentroant reecucend plaasma chSloero4l5vlneesEpaeceSbey 2s3%h, ePrisoansd PFPSdaare7d03chwoelessteraololoarg.er extent han PRBS (5<0.001 ak both u EE HE=-T= sg ~-PFHS i3i. ga NG zh .2 Er RI = mcm re a[aa] fee as aa] I I ElelSe E e e e or [Fenofibrate| 0.721| 0.001 | 0.007 | FC [pews 10 52610.|0<0 0.01 0 | Ee [Pres os74 | 0.003 ooi0_] be [1 pros 05 |<o07 .001| <4 0.001| ES}E ES [1 pros 015 <0.001|9 <0.001 | p26 31403 Mechanismofdiferent PATSGopn eksd amnd paaprt5otee1n5m0r88eaInAploES-CsETP mice Pl(raessmpaecHiDvlLy olyeve+l5s2w%earned i1n5c0r5e0a,sed at t= and weeks In the fenafbrate group CCPoFhmBopSlareterrseaaatSmeetnrhte. sS3honordweeldwaGsnrkootusofigurnkiefisscoattn.tePd(HiFfSeErSeanntrdepsSlpFaOesScmatsegWnoDTyLc-3achn0lte%ystadenersosle3o4rlee%vselsPHODaSs CleaSnsaesowntd-a0r0te,berCsomvpaersed to FBS atment, PHS nd $103. ae Samicanty When comparing PFHS and BFOS treatment, BROS significantly decreased HDL-cholesterol to a larger extent Figure 4.17 (p=0.028 Plasma aHnOdL-pc=h0o.l0e0s1taetrotl=4 and 6 weeks respectively). a0 oe a2,5] [netn Ea gr PHS. 520 $21s r . :gio = : : fios 00 4 0 1 oz 3 4 5 8 71 = 5<0.05vs.convrol Time (weeks) 438 plasma wigiyeorides Values are absolute values (mmol) and are means + 5.0. from mice per grou Individual plasma triglycerides levels are given in appendix VI. piss I F" ee =Io 7 An +5 Cr =eee e+] on eTene |oesa5|| area CA r a = par 3203 Mechanismofdiferent FTASN' onplepieandmeIpeorp5rt1si1n6m8et5abolism in AvoE3L-CETP mice [m rr m F--T] r----] [Controlvs: m [Fenofibrate 11.00010.10 0.0 0012| e fe1 ns 0.17 <o0.02 01|<01 .001| Jiro 07 --|<uoot T<oser] [F[1 peeass 0 1 0950 6 0|"007.0 7 092881|0.00 6 2.03145|| f[p1 1 prrooss 0 1.115 o0e.0s15 51|"o05 .0z02 1| weAepeekctsrtehaoetflm.ernetairmoeunep,s sFheonawneidrastiegnidfeiccarnetssreedducptiaonssaintphlvacsemradteisgyBcyri"e6s0%ata=nd4 7an3d%,6 rrEPre5eassp5v,eciaPin.uFdeSt6yPa1np%sdo0aP.aR0nO00aS-34PraWeRnasOdStBkmpSedeoneGftr.0err1see5sds.eutdcmaetaswr1sip2lp4aaensadwmraebaeyetkssAreaiisnc,asep7s-910%.I0v0ae1nasdiao7rneed3sp0SepcotEa0itv.Ne0l06yr3bawyBnete4kPb4sPe%Bo,S6f aa(iteae0en)aiWoi(nn5e0-ip0aa5f)ranitcnoegws,arwhdadrosuFssHeteSnyascentewPieFeOenSsaGrroouosuv., othttd wPeFdSsG3roburp,daBitneats2gn6fiwcaencsa Figurea1s Plasma triglycerides ` 333s E ii g rceornettae hTrooees E z2 XN N ~ 0 , i 4 0 1 2Time (3woaks)4 5 6 71 + p<0.05 ve. control p28 HGS Mechaofafferent PAS' on pi 3nrdepnth mtI Ab PGES-CETP ce 415 Upoproten praies aaLSoE Eoo P ont sAama Ea rhno.oTns yssonmstsh4aepsoAse Booonm a aFo ae nd 1750 Aa er4 and weaekssof eatmen, plasma chesteoreeels were decraeased ina the WLtthe erEeeirsneed 70nsa3heSraeSdmnOyeLaSeeohcnooLcnhrr8eteeHaaAsr bFoOetE,PSBharoomeoslenapo mrcsosn e0pSsspe tHDanoWotLesth a me ratio 2 an Fours 415 Lipoprotein profies i2 -- TEmFet] p|lTTEoEm eve }io w Ns A Wl TT NeT teon Nme foo J \ al AL aol TT E eSe reT so ER " I" " gfe " 3 oo 1I I3S N\\ oI 3 o A AN TT eswn mow TTT e" e p28 M203. Mechaofndifesenmt ETAooSnrep'cdtannudmpbaeprro0t3e3i.n12m6e6t5abolsm in APOEDL-CETP mice 41.10 Plasmafreeglycerol VIanlGuheisduaar)epalbassomluatrevsasluiecsr(mamolle/vLel)saanrde Gareenmeianaspp+e5n.0d.Vfirlom 8 mice per group. rce'o Aw=w t es= ww] rd I r elaoo |] 0a0n1 E I FF le] ocoot [m re m Fr r --) P= [Jf o isspro o--oss 2r 1--||--<<oo[i .o.00m0--s 01T||e o<oo<] .ros00no%r1|| ToT rss oTs o oss| f J[pJ prrooss o |o toe |i |s ooooa0s1T||e s aoooori0sa)|| B5wFuee3tne%okfastatrnoa1dft-e5e6,4wPa%eHaaSke8sa1n-p(d6lraewPsseFpmeOeakcSsi)fvs.eaheloPywEgeGBhdSycses"ir3hg1aani%mf,eliedcv-aeno5lts1ar%newsde3ulrnceedtnito4nnad3ste%cisnrogernaeiseteiocgodoltnywclteeayredokGlwseeeoevrnkeedssnb(oyOtfy24o16ma7%n%d,t)h,econtol group. PPEioFa0nSi0f0ca1anndtaPinfRdeOrSpe-nd0ce.ec0sr0e1waesreaedt sfteroeeden gbwleyetceewkresoelnalntehdveelPps<FtOHo.S0aa0n1ldar3gPenFrdOSexpGt=re0on.utp0.0t2hanotPFtEaS5 (wreesdpesc)tiveNloy = p.30 3ME03 Mechanismofdiferent FAST'HOopnrpoijedcannudmIbpeorpr0ot3e1i1n2m6e8t5abolism in AGOE3L-CETP mice Figure 4.1.10 Plasma free lycerol 0s Cont = p=aFaynoftrate Sos prporss goa go2 zHY :x 8 00 4 0 1 2 3 a4 5 6 7 Time (wooks) * 90.05 vs. control 4111 Plasma free fatty acids VIanlcuveisduraepalbassomluatfervealfuaetsty(amcmidalleLv)elasnadrearGeivmeenaInnssp+pe5n.0d.ierVoImL.8 mice per group. fA ear a wom o e a m 5se| = A [reevasr a dii e 050 e a 77 oe Soao | oao%s oTowr | ooax| o|me m F ee T ) [r[eresmotfe o0.m721[Tooasri[oome]| ffrpreoes 1 1050 9 ||<<o5 o.000011||9 <<oo000011]| =[Mose Tom |ores| Fe fp1 p ros o 0m7 |<oe9 .0s01a|<t6 aoe0]1] fr1 ros 05 |<o0 .001|<s o01] x M03 Mechanismof ferent PAST'HsConprpojdecannudmpboeprr0o3t1e.n12m6e8t5abolism in ADOESLCETP mice FS{rFneFeHPSfRarOteySspaescciitgdniivfleielcvyaenlbtsylyw-e4dr1e5ec%rseaianmsdiead4r8fI%re,thfeBaFcOyoSnatroecls,pelfceetvnieovlfesilbyaratbtyee -a43n7da%nPdaFnS6dSw6ge0re%oku)sp.so.fBtortehatPmFeHnSt AGPrFoeuSprgbrwuotukpasf(9eo2rf0.t0r0we3)se.tamekntthneoPsRigOnSifiGcranotupdisfheorewnecdesSnwiefriecsaenetny bleotwweerenFFtAhelePveFlsStohranPRtOhSe Figure 44.11 Plasma free fatty acids 14 G=oFnanoof!brate g3 z rparss Eo pros 2Sos Sos N i i zo02 * . 00 4 0 1 2Time (3woeks)4 5 & 71 *p<0.05 vs. control 4112 Post-heparinLPL and HL activity VGarlouupe.s aIrenadbsoulutpeosvtalhueepsar(iynmoLlPLFaAn/dhrH/LmLSc)and avraelumeesarnes &givSe.n.inraopmpe8ndmiixcXip.er [row em oTPTR 1sty| acy | Fd eerr re al w[l a23a [3] p32 SECS Mechanismofafferent PASm' oneid anndaInoptreotsenomestsabolism nApoE. CETPmie [rerT se ave, | aon EeTe o [Fen|f<0i.0b 01| ea <o.t001e_| [pes 10.79810.001 | [P1 ros70.02 0.001 1 | [F| es"<o.|0<0 o.001 1| eee] [pros 1 <0.001 |0.001] [Pros "10.00310.010 PpooisatnehelpairzainelpaiBpyrootaeepa7s5e3acrtley wnas sreonmgyinduced4 aeeeeonntaretrsepsmeacn (by rTosne Saoonece0by S(p2E0.0a9nd S30A cores FOS Samy Second--h--e TPOEES Thadesigpnifeicantsloy o0we5r eve1s ofoLeaSn0d03Hyrceipteyn2scompare t PFHS (0.007 and Figure 1.12 Post heLpPLaandrHLaictinvity 0 2. | rere mControl E25] 3Ea| aw"emPrFoeHssS Siis . z x 7|| . 5f 3 had ca4 : 4 4Zs ii Ee o 2 4 We f-- we +5005 vs. cont p33 363 Mechanismofaiferent FASr' enlscdanaumIbpeorprot3e1i.n17m0e8t3abolism in ASoE3L-CETP ice 4113 Fecal pias VfRraeolmtsa Sa{rceeormaebb,isonplehudytteaoegvraelasulesps,e(bulGemraaoud1s0a0tan3gdrcafomnySmAoauCcsUcsE,/dUeams).peopcrtlvrsle.yl)aVtaaenldaeaslree.psmre(a(%ncsiof+ntt5oat,a)l Cagepe ime pot ar gen i append iT Fees ws wr tir deToT1n a5] F II I 5 F os + STH 8T 85 1 &F [ome= r TaTmeer|oo nce |sics" iss| rov: es| fTI oermeeTs0|3o1i0sT]o--0s3sv | ems Tomo | woos[e ose | TI ies Tot1sn Tso 7 oan] ES TC C.J Jrros Toss ass ooo |osu | SSeNocrcetfaewscnarletmnyeauctflrreoanewltseosertsaertosbil,ys 3(ol8FfBe0uSsn,rt4e4S1.sP1%,H13a8oPn)fd,HS-SnF5eOat0Snh%dertrFrefeOeascStapmleeapcnrhttyot.uoTssotte(arToalbusrse(f4au1dae-14s3.0h11eF3e0cn)alvwebarlse eAlnthoounghethoeofpesnawfseateSogrmotuepasmhyowGedearseomfeowhmatth hicghoenrtayupacid(euxrcreetion4,1n3o6)eof te 2 p.3s 803 Hecho aren AS onepdi amnd ltoprSo3t3en13m05e3tal nApoE CET mie Figure 4.1138 Total neutral sterol excretion n weanior o 58, arpreerss gZiin | TSEE 2g HE 10 0 + pe00s vs cont eS wesks [E[r en[m amesTe een[y oe | E EE t RE E a e e ee eee r a|| prepa feos ose T0002T0004|oms__| CTppehooremcsaeftlenctiaaloGgrennoeeuusxstcrrlte(st3teaado5r%co0lhmecsvo5tmsperor5os!3i.t7wi%aons. sofiTtthheyfobevuntefrstori"afmtiecssairmnoetunyptnwsesousspos.meohwstoacwtoemcphranneegsedt,Ssohtmheee M 5.35 3803 Mechanicof deren EATSH:r1epc3numpbearp0a5i1n20m8e5tals i ApSESLCETP ice Figure 1.43 Total phytastrol excretion 6 5s 535 igee . 2Hg8s 5)s2 3 tt hl hFcoeernice rove wpros 0 5 weeks + pes vs. coro! F I E 5 Esi e se ee ] F] m a| p e B Ee e e a eee aoe | CGOnrlypEF7F0F3oStrSepshteimeeanntraflecntceersdnsfe,escaGls1hpgh0myatsovessra6sr4ls.3c(o%1m4apo5s%t2io0vns.552.2v3c3o30m)8p.aa1rn%de,deatsodpetcahrceeaecs)eo.dnrl P) is i mR . --= g pros siHE iSffEg : i83 22 . or [w = w TeeTe a C=FTW TT Tar a] E C E E E Ef=E=SSe = e See TeE e Ee EE e Eee e Ee eEt Eee SES eee . p37 SHEG3 Mechanismof diferent PATSooen Ipss manpiaapoainametals ApoESLCETP mice Faure 41.134 Total fatty acid excretion a0 ewotmre 5soo 3 wprrereoss 332400 if I 5 5300 z38 | "100 0 p05 vs cone! tS weks Eo Fee NF He F 0 F Tse a|e[65] TEmE e o a Tero Tene oemeToane|] FEC eee GE == ==EtEcEr E m3 e me we | n C thoues cohnanNegoessatine7fsa5y eaocnisdccaSosAmepoossa5ia5wnerweehrseemasplo,rncRemSaods oef Cpiv thoe pmercevnstag7e90o)f % p38 39903 Mechanismofdiferent FASH'Gornepicdtannudmpboeprr0o3t1.en12m6e8t5abolism in AGGEIL-CETP mice Figure 4.1.13 Fatty acid balance 15000 gfFH3= 8000 8 on ic 33g5 woo H3i 2 2000 `=a=CFroainnstoretoblrae N abPrFoHSs v3 e AE +p<0.05 va. contra =5 weeks meso ram moussjon) | opurougs Fa erra S=ens es wI o pl rC os = = opis [Conv Fa|m ooe n] P--er--moi--n--]| Ferra foT [roso ps se a] ] ffoT orroes ou| rSTiheneaitffmtietanynttayci(cdohybaanlg1ae1ndc%.e (pfea0t.y01a5c)d. InTphuet -poaurttpuuatr) woaslsigsniuflilcoannattley inCcormepaosuedndbsy fweenroef.trantoex a scan 5I tt ttnA whe moveemre eoanrst FRE CEST Th FI WTgm Iee este ee [rencterste |oo0a| 0072 |oes |oes |oeoe | [pris | <ooor| <ooo1|<ooor| <oooi|<oooi| a = == == == === [pres Jos [ros 1 ooss|o7os |ous 1ooaiToo | 1 osm |--<oeo1 | <o0o1T--<ooos|<oo01| T0028 1<0001 TT <oo01|<ooos1 <ooos| r= a [o =Hi] me E . E ee r e eer A EE = m -_ = BE e= ni BEO hee anaeei t 0 Ses F fertEaI ET RE SE. eTAe " p.40 3203 Mechanism of diferent PFAST'sGorneicdtandumIbpeorpr0o34t.en15m6e8t5abolism inApoE3L-CETPmice Figure 4.1.14 Plasma triglycerides after Trton WR1339 Injection 14 ~Facnoonbrae : 1S| 2 TThoemsss e21v9 pros : gs sg s =| 4 A 5 24 A 7 _ > ny 3 oH = Ti2me aftr Tr"it0on WR13396Injectiona(0min) 100 +p<0.0vs5. contra Figure 4.1.14b g1g6u s: ie gn 3s $s S$. EI3 z VLDL-trglycerides production rate . o =wFoonotnirate apprress wpFos. x Zo * p<0.05 v5. contol pat M462 Macha ofSern FASSnpid ned Ipspon?meals In ApoESL GETSis i ry [ones| her [orm| I e fr o=] 2-- er-- ] o-- -- e ---- Fua bee] = 49 1 -ee, fpE W ePtreeesceer s mi o F l aseal [lli cere a r| r m | W7 el [ree u | I a E p E -- s-- T e ] eaes] SE L =e == b= | 0% | Jpros 1006s] ai E otsaE .showed no alec onRAde nove Apu soydrtioA awaati(F1u8Arsi4.o14).gothSety naesmandscia otmae., sFiS moowoenses5 scaeeysessedsnaApso psa rat, AESe Yan FSr ronge keeAgtaesiwin.eS(aegsecvtivleynbtyo78o%reanmd 837h) +jr45oamtd FOrSbhiatedsiceadnty edd de nev Ap sshd te and TG rchction " p.a2 SM203 Mechanismof diferent PFAST'HsOopnroijedctannudmpboeprr0o3t1i1n2m6e8t5abolism in ApoE3L-CETP mice Figure 4.1.14 12 es 1 . igE 5ze 3k EA + Denovo ApoBsynthesis caFoonnofvirate apPrraiss apros 8, pfrocus : Ci + p<0.0v5s. control Figure 4.1144 TG production per ApoB 25 q 20 < T2 E E515 . EE igss e 05 C#Foonntortoilrate a"porross arros 3a3 00 *<0.05 vs. control p43 M03 Mechanism ofafferentPFATS'GsporiedcannudmIboeprr0a3e1i1n2m6e0l5abolsm nApoE3L-CETPmice re es Te Te [on Ton| Toms oooTor Toon | sot tou] Cr -- 7 2 | I a1 i in 1. 1 | [Ferereratevs [res 1 oooi[oui |<oeor ose 00s] [pros 1 <o0oi| <ooor| <osos[02% <oooi| ros 10007 e003--|ooss |"1000 | eas | EnVLiooDpsiiLdctScraoaermicopceloneaststneitIronynaoanfddsifiIisenorcleranaettteadsfeVrd0LowDmMiLignlc()oysn,cteorrcloiatldleecdsuilncVaotLaneiDtdLet3nstr,etuahrtmeemoselpsneutc1mtigvorefolpunyepersbw.ynley`wF5sleyn5yno%tfSihy3bennrstdaihtze+ees2di6zdVe%eLdc.DrALePsposSoneS,dd aCSgrenseitceraranotlelusystaenirndcrpcehoaomsspepodhsoiltiTipioiindvscecbnoyindteeAsntGIc,noVmLePDnFLtO,S.rbesyepeac3tt7imv%ee,nlytbPyFIHn+Sc1r6e4ass%he,odw+ef3dre6e.%a achndodelce+sr7tee4ars%oel.,d CWIonhcmerpneaarsceedodmftporaerpe8cdh5o,lteoFstHetrhSoel,IPnrFdHuicSescgrseomaurlpl,eratnhpdeahrPoeRsOspShaognlrdpoiPudpR,OSsIhnlodawcreogduevpaeanorriiesolsla.artgeedr pVaLrDtLiesw.ihA Figure 44.1.14e Lipid composition VLDL a onrol a=Fparneostrse ;2 . arpreowss i3k 52 22 83 % ox =! x | Tet chats rnhtsorlcholsctot Tan4i Phsshot4ies *p<0.05vs. conte p44 3803 Mechanismofdiferent PATSN'OopnropjedctannudmIbpeorpr0o3te1i.n12m6e8t5abolism inApoE3L-CETPmice 42 Results study 2 421 Markers of general well-being mlNaaorcgrseopresccniofpitcihcceidificefanfolefrtesbnircgaentssewwgeerrroeeupoobbassneedrrvveestddrodbnuegrtliwynegeenntlhaetrhsgeteudgdryo.iunpAstt.hesLaciPrvFieHfriSscew,aenrbdeesPivdFiesOisSbltyhgresoouIpmv.eerwsOhnaneto mouse (mouse 21) showed some white spots In the ver and bile stones In the bladder. 422 Body weight VVaalluueess aarree gaibvseonluItneavpapleunedsix(g)I and are means 5.0. from 6 mice per group. Individual [oo [ow1]6 23 T1T6 I-------- -- [rFenoofibrmate| 0e50r41w0 co8 m|1 0co5387]| f7ee2s C 1om T WCo 7 |os s3y || fe[rpsseTesoeowmseT0o5s3s7T0o5s3s]] Jrros 109 T09|3 os7 s| : frros1oss|oss| oem| dDiufrfienrgentcheessbteutdwyemeincgeroguapisn.ed body weight in all groups. There were no significant a p.45 3203 Mechanismofdiferent PRAST'NsOonpropjiedctaundmbpoeprro0t3a1i.n12m6e8t5abolism In ADOE3L-CETP mice Figure2.2 Body weight " aCFoanntorfoiolrate a"pprHess 2 8 pros i : 3 . | 2% i Fd 2 " i 0 1 4 Time (weeks) *p<0.05 vs. contol 423 Liver and perigonadal fat weight VVaalluueess aarree gaibvseonluItneavpapleunedsix(g)1.and are means % 5.D. from 6 mice per group. Individual 5 [Frereemrare TM 075107 Sol e1e76 Ton| of oSIomHr 005 70537s 036 feT r Tres e0 n| a00 c.t0om 0mb0|0 |ra0e 0322 1t00m 0e|| [Ferotorse ve [[pprreoss J|ooeo0szT|osvaise | [rpreosm--| o.e0c2 | ocosr1 | pros|oo|0 oez| " p46 M803 Mechanismof afferent PTEAGS apnrepfieactnndumibpeorpr0o3t1en13m6e85tabo in ApoE3L-CETPmics WFLieevnecorkfwbeoogtfhettsIrnecwarteemraeenstes.digenPiRrfEiScwaenittgehaittnscmrebenyats+e2dd3iid%.tnhToethfernFeasHfuilSbtraaItnn',d PsFgFOnHiSSfiagcnardnotuPypFsOIsSnhcrgoerwaoesuedpd,.aArIeovebrruss.4t SiIn'nodnipicectraiognnotnIyandIaGvlfefrefrawetenitwgfehirtgoehmtrtehwsepaesccotniStvereoellyn rbaoyutpe+.r11LP0vR8eOrSanwdealng+dh1t0sP7F%I.nStAhteKrDePOaUtFmGSeNnta3,hdStIhPiROsOSd.weogcsrroeuanpsosex TWoatrwearSegnsigcnaiinctayntnyigGheecrr9e5asceodmipnahreedPtFoHtShaenPdFEFSOSgroaurpo,upsw.hereas weights of perigonada Figure 423s Liver weight 5 =Corre . =aFparnsotrae 5 pSprronss zs _ $ a 3$2 x AHEnAs | fo 5 o week 4 + 5<0.05 vs contra Figure 42.35 Perigonadal fat weight 12 5: 10 gos 0 5 04 & 02 00 + p<0.05 vs. contol week 4 as ==Foornoitirrste apprross apros p47 M03 Mechanismofafferent FAHS'Gosnpropjdectamndapmopero0t31e.in12m6e8t5abolism n ADOESLCETP mice 424 Foodintake DVaarlruoesupar,e Iabnsodliutoe)vavlauleuse(gp/edraay/gmeouosee)vaennd anreampepaennsd+15.0. orrange from 2-3 cages Forman Gramm | mee] fr sa oa ea [ooToT5341 or [Fenofibrate staanv)) [a] fs saronogn) Pd r eal a ] a: [[e Esmree er] Grmeesks)1] ToeToon [Een1o1f00i0 | be0a66t7e| ffooT rrsoes o oam To oossoo|| Ferre frr rrsoss m orbeasrmTTo---- os-oe.] [rr frros T= om ] oso] [risv Toros wooo 1 oso] A groups showed sia food intake during the stu Figure a4 Food intake 5 3gE. g ==FGaornrootrirae a"rrreavss arros s 1 e i: 3 1 o i 0 04 34 Time (weeks) a pdt 3903. Mechanismofdiferent FAST'GopnrIespetannudmpbeeprro0t3e1i1n7m6e8t5abolism in AsoE3L-CETP ice 42s pmmaaT (V8almuees apreeragbsroolu)teava2lu0esan(dULL4.) fom measurements in paced plasma samples pr group a[e eF rieE Pny errtE wee | ; po = i i e TGAroEovuep,2e0,BuwtAeePeArkHsS4tahwneedeckPosnRtOroSoflSWhreooswuetpde,ns,whiohtwheerdecsaopnehtcioglthegeroeAuLpTevSleelsve,lma33d5igtchhoeemrpHaoIrnnceerdesatsoie s1tmhpsathAseLarT RE Figure 425 Plasma ALT a C=Faonontrste 0 aroirsse I arros 5 5i 20 as 100 w oe I o o 4 Time (weaks) 426 plasma cholesterol VIanlduheisduaalevalboseolsutaerevavleuens (inmampople)nacn1d ae means & .0. from 6 mic par rou. eere--] I I = +5 I Ano | ou r = e w= [EZa [5Se] ao p49 303. Mechanismofferent PFAST'sCponrpadcamnudmpeoepsro0t33e.in1m3e68t5abolssnApOESL-CETPmice reemre m peee] -- [Control vs: [Fen|o"f 06i16b|r0a.0t02e [[Jpppo rreoisss 10.3om o0o41T--o0v.0o0a041]s|] [Fenofibravtse [pres | 1.000 | 0.065 | [TrosrTeoso o[0r00]1] [ros om | 000 | rAs ewasaseten nIasteudyt1,ofalmterenattmentFegnrooRuypastsehdoewcerdess3edsgpnafscaanchroeldeucnteiroon Biyn 3p5a%s,a P"FES7,5 aPFnS aend aPhFrOS4twreeeaktsmeonftrreedsuecendtplasma cholesterol levels respectively by -16%, PSrha PHaOnSd sFnOoSweddecrseamsead cmhlhest.erl eves to 3 ager exten than BFBS (9=0.002). FHS Figure 426 12 To3 w E3 s 25HE gSe 2 a2 . Plasmacholesterol C=Foanratrirae ! mePrreiss acif WPFOS 8a x iG .x i : i FE : Time (weaks) 4 + 5<0.03vs control " A SE ---- [-- rrmiEmE--E -- I [rp o Ge DRIr RSEEr eLEiEnEE2R [Controlvs: [Fenofiorate T0537 16.002 [pT ris 0530.7 026| [pres T0957 T0015] Jpros 10937710.002] frros 11.00 10.002] TET e--s--------r . 3.3 . =wC2m E, I.as i32 2:gFe d 5 = . . .i [7 Time (weeks) [a rer FmEe)] [Fr EE emr ee [Controlvs: Trencibeste11.000 [pTM ersT1.0 1"0 0.00 021 gra Fenofibravtse [pres 1 oe1s | [Fre oo37 Toss ros 1 oie1ooai| [1 pros0.5130.17 60 | 2 52 M903 Mechanism ofdferent ETAGonpIrSojdecat nnumpboeprro0t3e1i1n7m6e8t3abotsm In AsoESL CET ice rAelsttrmeeanttm.enFtengornoburpasceshdoewceredassiegdniefimcanat rtediuycctieonndseisn bpyla6s5ma%.rigyerdes at 4 weeks of rF"B5tS5,%eaPtnHadSn507an%3dSaPEi(OprS0.4t0r7we6ea)et.kmseFnotOf rSreedssuhceoenwdtep.dlanPsoHmaSSgrndiiegkrcaeennrtsdyeedGsielerveeClnEs rrtoeresispgecclteeinvedesleystobeyver-s3e7%5r, Compared win PHS ond PES Figure 428 Plasma triglycerides 4 z-g } 2, 1{ rCoonnan aaprprirrdosessd $1: peg 5 8E # Bl; x 0 0 4 Time (wooks) + <0.05 vs. control 429 Lipoprotein profiles DUCephroepcsrrtotweesri(n(WEwhetr6ceosIuepmca)rapt3aenddrannooaspsuuaoptIeCrpoodds.se WcTeocuGno.rceoVrualruf)eoscmiaeoeanssaur+be5mleaensVtsvLanOluGebso3o(e1md4k)p2l5raosmma 01137 as large HoL (DLE) and 17-24 5 HDL EDheaepsrcoocfnhetlsroelasreaerroamulno.vraFseenwsaarfethrdeeasconreemdaePseaHdsSiinnShehxoepwVeeLdrDitLmh-eeLnDS1Lr. apnAegoeekstrInawonldel egkrssouorpfstlroesaectdmuaecmnitpo,ne,d SlSepFspOseeSsrrsoaoxncaeenmdoftfaoalndaercPgrFeeHHaSsOeLanALdpLFaOrtSt.oea.HsLeewrasexitnecnrtecahsaend nPAhS.e fFeBnSoidreoceregasreod,VwLi 10te0 rtWhhfeerOleLaosfpPto7nk8eFHPseHSeSmgersdoeuetpomeHiOdnLctrLoea(dseercrHgeOaLsHeOsLoH)mDeLwwhstaoti8,nebcsorethreP:eAxHtSenatnndaBnFO5SECsStraonngdlyntdhecereased hienchheanCgheasngnetshinIpplgpertseiennsls(kAeprosB)-caonndaiHnDiLng protein (VLDL-LOL) and HOL) are n ne st p.53 IMH03 MechanismofdiferentPFA"ST'HOponropjiedcannudmIbpeorpr0o3t1e.n12m6e8t5abolism in ABOESLCETPmice Figure 4.2.9 Lipoprotein profiles a i Ju=]: 1s Py 0 [SrA / 5 wctiw on mo 2 ful #Thm we If3os Ee 0 Y f AS" 5s 0ncton ow om 4210 Bilary ble acids, cholesterol and phospholipids production VIbianldleiuvaeicsdiuadar,levpaahblosusoeplshuotaleiepviagdlisuveeasnnd(InucLah/pompilenen/sdkieoermoXoV.aunsdeafroe mbielaenflsow+, 5n.m0o.l/fmrionm/k5g-7mmoiucseepfeorrgbrioluapr.y fa C ar p w wm o a -- Ca -- ] -- [a rFemrererae a ErLoSa [E ee s] HE oLa| FAS ws EO ]5] es [oss 07[039 |00s | fToo1 rrrisssm T0. 017 [[1 B0o.0Em08[|5 0oC0aC9E[|W6 0o1oC306a|| [Fee f[foFreeoss--1j|.e0tso3o6o[|0u o.0s3s6||oos.se 0s|[ooamr|| [pros Tosa |toos|075s | Lovo| ShAiiogsnuiwgfaishcannboteIsnfncliroefwacwsaeanstthyseodrmieefsweuhrteainnttgiftnracotrmaeatbshieledeclIoonttwrhoe(lbfyGerno1ou8fpi%.b,raHpto=ew0eg.v0re4o1ru),pa.afelnolficborlalteectdiiodn points, 2 pss 3M803. Mechanismof diferent PFTASN'Os pornopjiedctannudmlbipeorpr0o3t1e.in12m6e8t5abolism inABOE3L-CETP mice f(rPoeE6rsHipS+le4ect6vrcee%aal)lt).mc.PeiFneTtBdhSei0n-arc1nre5edsaumsPiieRndnOgSbaionsetdnaflo1lw5obwe:i,d3e0tnhfmoilsioewnwffwhseocestsrsiigotnsnhiofeiiScceaaannntlniloucywlo.danitfwleayrsennpctlrafecroeosdme(dtbyh +cto4hn8etrPoonlHdSgr+oG5ur0po%u,p Figure 42.100 Bieflow 120 3 10 a=pFraensotrse Ei: w wrprroiss fw i w fy HE i = 82 045min 1530min 3045min total Time bile collection + <0.05 vs. contra [mesSo nee ereleer= lTee--lr--ms----]] Fd errSrrEa el= e 3 I t Eo e a ! el Fs CC de wlelS sEa Tlaewsl[sa]] PoSo esnem sen s [Cows [ramets{om |ose1.180 0200] [Ferormevs {[[ceproerssm--Jooo3snm6Tooosn2TCooasrresT00E03.T71|6] foros | oie | 05s[oss [ois | ros Tose [oemTos Tos | 5 p55 SMEG3 Mechanismof afferent PAST'aen Ied amndaIbpeoparten13m00e8tal isApo S-CETP mice oAtwheotu0ogwh vevngfrtrrocartSoecnanadrnooat.ldesseerreexteantrPhEeS canodnPtOoSuss,eemFedStsdheocwreedasneeblSear3n6dple Floure 42.106 Bll acd low 1200 : 23 1000 rpSosas n 2 a0 . WPFOS. E 600 1 T 1 zg 2=: 40 ]B :*> ao p{ 45min 15T%i0membiinlecolle3c0t4i5omnin total + p<0.08vs. convo! pfeemdym mse) Fr IAL eIT R--r ----] A m Feree e wiI w 5 [5] ra2i{5o s | i [Se a I I Ti EE PrTow Pas Ferrer] [Control vs: Jrenofibrate10.247| 0.030|03% | 0.180| F fP oe e r cJoe m oic -- ort TTe |e ooo1m0t a e setcoone a omom uo]| [Fenonbravtse [pres | 0.247 | 0429 |0702 |0792 | [ros T0626T0366|07311 0534| [pros 0.67 [0.635T08761 0.87 | p56 M803 Mechanism ofdiferent PEATSHGopnropjiedcannudmlbpeoprr0o3te1i1n2m685etabnAOoE3iL-sCEmTP mice 5CAa2Rl0he.oc0ut3ig0o)hn.bpiTolhnaesy,caplthcouislpawhtaaedlsftaiodtnaylflPdoiwofswepraehsnotslofimrpoemwlhtohawt, chiononcwtrerevoalesreg,drowiunapsthoneto(fte1Sn5iogf-nii3bfr0iactamenitnglyr(ocbuhypa+nagt5e1adi%. , GF7rF6oHuS%ptorrreesabptiemeceincetloiyln.ecrcTethaes0er-de1sp5uhlomtsiipnnhgoaltnoidtpail1d5sf-hl3oo0ws,pmthihonilsaiwdfaksfltsohiwegnwciafasincniausnltoay swdiaigfsiercpeaanncttelfdryo(imbnyctrh+ee8a8sceoandtnridonl the PHS Group (by +68%) PFBS and PROS shamed ho fects on bly phosphla low. Figure 4.2.10 Phospholipid flow 1200 -1000 2HH3HA a0 52E2 ow gE 20 IE 8 i =FaCnoortrirst apprriaesd pros ] 4 4 | 0 05min 1530min 304Smin total Time ble collection + p<0.05 vs. contol Emie g mous) Tr Tr rer T rr [Tre e] Te] rFe = eerrea wTwllo s15ss7a e || mseox | r em1o | [wwoe m ma e Se iH e SE 0 5I ss x M3 cnt ofaf 15T 01p R 0 tnmoti SEPmi Fes orTen ou] [Betweengroups-- 170284"170366 1"056410358 | [Control vs: JrenotbeateT0792 0.42 T 1000T 05891 [prs 10.24710.177|0618 | 0.240 | [pres Tosi[0126|1.000 [0420| Jpros 0.23410.545 | 0.628 | 0.295] pros 1 02021 0343 1o7ss1ozes| Farr csr fo, scaargs wr sn even gous. rare32.100 hoetorotw 0 Even ow pri i i8 } wpros 55i% 4 i3 j! 1 ] 2 . ffi Yii |:| ii ofsmin | 1T5i3m0milne|coSldtmonin| toa scams. con " ps8 M403 Mechanismofferent PACS ohn gidanmdapeapSaSin5emaestals i ApOELCETPmice 4241 In vivo clearance of VLDL-ike TG-ich particles and uptake n tissues Vroaolouee:s anrarurtegaluinnvevovaalsvueasrie(sofSorelnjoircavplpdeo1ns5e)dfaonr1.dpraesadnecsay aSn1d0 uoptmake3-in8acfeeerpso = Teeme Ts ee s s Te s e] B BE [oe woTa o2 mTr om 10 e 0s 1eoreFs]m| reeee [mm] F er S 1 cus] CC =F E re t s] ] Tf pse s aTm ae] ]| pr -- SR ] -- DE TTFGe"hnoCdteabaarrraaaennccSe)ohofwwLeadsOLtshkgneStrkCoanhngteiyslcrleaarceanebcldee,d(1plaeirnceeesvoItynnPpeElrNaySs,maSwo(r3uspesaasmekaPsEeuGrSe af$ror2d V1P8OL)S rowed s compen Sema 0 GSInecrfeiagsusrn"se3t040.%2hd.ae1erc1rbPes0tPsh3eeEdSo[T*HrOS]-hohtorwlioeldfeiln bhBalef6-rl9ie%fe.n(s=P1F/ofsSl5oap1ne%d,fFigOuwrSess4.a2tw.ha11srae)+vieSsossmhTPocwHanY.ntrFyteneSofoinbagraeltre TThheshaanlalPeEGoSf oWnLDtLhIToGndtidrneot.sgifcanty dies between PFBS on the one hand and = bso HD HH B Sy T TTRSRT ke Figure 4.2.11a [*H]-triolein decay in plasma 100 pegs HfHio No 3 ES --. - EE 1 . pooemom* 2 P Time after injection (min) Figure 4.2.11b [*H]-triolein half-life i po - tie i pros Ez M 2= . Eu . : a . i L Foo i SR B gri Tn g NTaA AA * p60 Het Hecho a tet #45Sasids opie aati n AESCET ice Emer =[om[oe[oe[er] BO1UL0ST5howJepL.edosncrnytaySdecgJreatses {otlkunngteeaakhs npoh rs aodi osreeleeen (oy r raa r r TTeesrT Pe e eo|i|| rw r e mle Pe w r e e ws we [3] [F[eTve T enTee Tw] D p a e e m Te em ar e [ews 10004 | 0017|o00s|oo0s2 | 0082 | pte ee eeeeee)|| fros Jos 10792Tose |000s | 0004| 0004 | 102871062Toto TosaT0281] Figure 4.2.11c 3 "I" HE] Z83 2 iis: 2 Total liver [*H]-triolein uptake raern udPFHS. : IWGhEE * ;i 2 . SE - pot S803 Mechaofdiferent PESAopnSIpe' amnparoters t5aiteals in ASES-CETP mice Figure 42.110 Total asus CW]tilan uptake i.12 . ig23 10 8s 3 ig ; oFenoton = wr=PFoBpSs. 1.: 4 8 : i " 2 ; i if heat spleen muscle WAT + pes vs. control TiEFhReeOncSacialerenaarscaPnIsc:NehSowogfedrdoeVurLipDaseLr-rlcSis0keoenw.oa["es`sC1]S-1ncad6hoa)mlsessaPt,eRyrOywSlhnSeoherloesewassteeedpspa7a0ritliacaSlnheres PSf(EcaRosaSrraSsthmsoeswtahesdugcrroeoucnpfeoo)ramnrdVp.oLaDuhL.neec IFEnunifeihguvaraett4sS.32S.p1on1ffinratnheetss[yp**GeCo]c-scc.haoslFeesOdteSGryE!whaaosllfenaitkee Sbhagylnf8-ni0cif%aen.(l=yP1F/rsSleoapnentfSigruwreo4r.12ht.1e1ceo)0 mis)shGorwnoo.y EE me ss ssseos fer TeTi Tr ar aTr aer] w A TESTA [ime |ispesspna pe ppee r -- I T E EF E E E aE E ra [eo eae] frros Ios ose 1000s |"T0004| ooos | [ fier r4 I r|r f| Feorr t ---- fe = E ] o-- =ar e m=ams--| -- I| E Er e a SS -- -- Figure 4.2.11e [*C]-cholesteryl oleate decay g fo Ec i2$5 s2 [59 . wemGonteh = fom orPeHsS `Time after injection (min) " p63 3ME03 Mechaisofafferent PASp'anrIdane d Ipopri ten metabolism InApo L-CETPmice Figure 4.2.11f ["C)-cholesteryl oleate half-life _ O200T E weeE n EI 150] "torress 5 $10 i 2s 52 L + pe0.0s vs. control Ta Foetraalibiavtre,5P)bSchaonldstPrys lShaotweedwa5sSIonncrieacsaedniuncailloneaftmreenstpegdroiuepns,+1e4x5c0e,p +FO7S4.% PFHS sohoewedtaasseisgniwfeircaentnlyedSecmraeanstedly["sC)-cchoilesotferaynlyoeleastetueptake in the spleen (by - foCsF o Ff Fo w+3 wTwTe &[| III a [rencfiors| te 0008| tooo | oslo |oar|ooos | smear e] on] freeme Ten a] [pres 1 oot | 03 |ooos | os | oom | aeso e vee e oi ous| [ros To00sa 01mTos oor[os | @ post M403 Mechanismof arent PAS' on pd ard pearnenameabalsm i ApoES-CETP mie Figure 4.2.119 100 siF2. s3- Esa L$3aw Z5s2 2352 . Total liver [*/C]-cholesteryl oleate uptake rEperrs e : pau. ;gi jiae a = [-- Figure 4.2.11h i3. s. $38 ize $58, TiE5ehi) EFl 0 Totaltissue [**C]-cholestery! oleate uptake Srroeeosmm erso : heat | splen E : muscle | gWAT [I -- o p65 3603 Machaisofdiferent FAST'GonpIropjetannudmpboeprr3t1e1n54me8t4abolismIn ApoESLCEmiTcPe 43 Results study 3 431 Maorfgekneraelwelrl-bseing IrNanoccisroapsseceacdptiicnclieinnrieceaflnenscoifeginsbsrawwteeerreeGrooobbusspeerravvneeddd rbdueartiwenegectnrhetehasesturedgdyu.pAs:hseavcreFiFfsiAcSew,arnbeedsiPwdFeaOsSlthGrsovauepm.rsbOnnaeo mae (mouse 23 snowed 3 granar r 432 Bodyweight VVaallvueessaarve gabesonluitneavpaplauensai(5t) and are means S.. rom 6-7 mic pr group. ndhidual Cr A rr we w H r] ] Ferrer S WoH H|e3r s |r3 H F i || e H o3s | |Sos Fh |9 Ig eee ag r s r ] [Control vs: [F[ enofibrate|p 0o.r3t1o8 10os .s38e3 T11 a"r03s1i0 || [Pres 1 oea0|oase |oss | P foprroossE To1 uoasseT1oe osaose 1|e o0i93s7 1 BTDFuerSaitngmGrntothup(s5tS5uh0do)ywemdica mgaailnledukodSyGRWAeClhRtnCndaecgeraosupesd, bIondycwoatsn Sset4ywe1e3knsdo2f, the o .68 He03 Mochi ofaft PAE S nd she en mtn nAGENCETP ce Foureasz bosy wane " 2a Hroeemuote Te mPFOS 2 ; i3z . o 1 . peas va. cor Time (weeks) 433 ver and porgonade ft wight rVosiaseaust vgeso) nd as me 5.0 rom ce er rp. Indl Ee [Fencrierste10.004 0.465 aE s se e oesaoer [" prs 0.00 0.02 00 | fpros "0.002 T0132 feos 1 e0021000] avesergwesrye dsmReagasarBynopcyrsSs5eTnd5e in5BthheBSeiPnb3o85ftEooOetE, SSBoPAAtRSsaend s0P5RSrooPuop SrPeeovnva . p67 HATS Mecha of diferent EApS aen Iidda pmpatretrsSineretaolen in Apo SL-CETP mice AEthowughoaydeScraennseeainnyperrgeanandal fhatewPiPhStrwoaststeoen a-fSe65r)PROS and PFS treatm, Powe aan Liver wight s wFeoroos rs s4 aPoFHsS. EN q 35 1 weak4 + p<0.08 vs. convo! Figure 43.36 Pargonadl at weight 12 5e 10 5HE En wvomn htroemss wPFOS 2 04 1 & 02 00 weak4 ! + p<0.05vs. control " Ren ro [a rea raE. [risingLee I 0 0 [Controlvs: eLl EE [Fencfiorate11.000T1000 | 2 Era [pews 1000T1000] [pees T0700T1000} pees o00 E000 fpros i0001 400] fros 1 0701oa00 | i: onTn 2 4 arPrroiss i:g 3 i i] 0 B . . x 5H03 Mechanismofdiferent FAST'GonpIrojpectannudmIbpeorpr0t3s1i.n1m2e6t8abolismIn AsoE3L CET mice 435 Plasma V(a6l37uemsicareepaebrsgorlouutpe)vaatlues0(aULd)4.rom measurements In pooled los samples per group [> i r vue Fm T o ve i a oTT ] GAreourp.&1weceoknstfrroomtotsreuadtmsentaPnHdS2 FanBdSPrFOeS ashtowe3d9Hisgeheerm AfLTInecrveeassetphaanstaheAcLo.ntrol Figure 43s Plasma ALT 500 facrone _ a0] aCwroprrrouesss ies =s a0 Ro 4 0 ] z sa 100 ii ai . 5Fa |i| Time(weoks) 4 436 plasma cholesterol ViandliuveisduaaleVaablsoelsutaerevagliuveesn (inmampople)nadndIV.are means + 5. m[p frFeaeorre l e ae ow=l n r 7e ] l s3 | r a a =e ar uFe a l al dala 77 ] Fl rom 6-7 mic per grou. p10 HO03 Macha of fren PAS' 0p1r9ed aannpersotoesinemaseals ASOENCET me [remerarFTeetepos|oomoesonrimsaows]s]| Tfox r m seroeosom wniowsooae rowe |]| ros 5 io oom| LAjSEonweo seeeneIneexpeorimeentws asandof2,reaalmrentt mevo--grrooup--es sShe--oewaetd--aSd oC--eA--rre--aduceti--on in Ta ere venment f745oarn t10Shdeprepnsrepdicthteeesde lvl 0 3 rer extent th PFS. (3-0.002), PHS Fgura 436 " T_3 n : os is plasma cholesterol i " rwhroeesone . aroovse :5 4 Se > a2 0 0 Time (wooks) + 5<00543vs.7contolPlasma WoL-chalesterol VJ alues oei abst vr alues (mi el) re meas 4 5. . hm 6.7 ie per re. - pt SH803 Mechaofdiferent PEST'rapn Iei nmdapmperotenemetals inApo 1-CETP mie I ==] rEeEe dw= e es[[aon| ne| oe|[o|a d fFoFs aa wai oa |] om [Controlvs: pI a re i= r o= e] ] JFen|c0.f50b21e0.a0t 02e| [T pens 062 10.0 002] feos 11.000 0.0037] [pees 11.00016.065] [fFp1 ErRoSs 110. .710 01"0 00..000 0022]| pros 11.00010.002] HrrDaeLmrcehtoRlo,onsebtyreel6i5lnes%vealosannwaoer37ve4en%c,eSarmsepecedacianvteryy.4GwFuEceEesSsksweressaWmtLaeneRaSinRtorhkeoflrenesfebnrra4eSggwmreoceuakpsn,tboyyf Wsinean coompawrheedntcoom7p9aSr,i,PEpHSSasnnddFOEDSS trreemantamenntt, snhsoSwead n d.eecshsanegdespwlaisemaS5O6L Figure 437 plasma HoL-cholstarol 25 z Lar. en :20 rarosvss g 3 15 $22 10 os Ix a i) 0.0 Time (weeks . * p<0.05 vs. control Lis ) o FO Rn wr m-- [rEr EE r r i aa = r a EEE [Control vs:" [Fenofibrate T0710 1"0.002 1 [pres 10502 170.008 ra [pers o620 0.002 | he [1 pres 071 1 0.0 002 pros 1 oro 1ois | fpros 1050210.009] a . p73 M003 chan of trans Ftmld eant Yeinogeos AOS CET Fpreass Mesavigieries . Srore 3 = igs osvsen 2 17 %2 | 2 E x 4 o o Time (wooks) . ---- 435 Upopratenprofies T poorotE ein wree seoparatsGeoadsaLr nmasyusp1re72a4(caAn.cuoVamvlesF eaesabn ostsvaluees (si5)proomm ne profes ae moer reeesds BtheeesaamsenaEnSHeSexpee3rsiSmesntt1 oandm2cADe ropaowkmss3koflaroupss 3 oy acne reeHco ohnrsvreeeemesemmasasaceroeSonseAoErsaMirortweeoanortpgrmeaonn of aes una REIT ie Figura 4:30 Lipoprotein proies " i" in i J3a or on IN a 0 - R onZAT Wol pIE , R SN RAR A FEE ETE Fe r e EEE [Controlvs: fIE= EERE Fenofibravtse [Fenofioate10.710 10.160 [pres T1000T0818] [1 pes 062 | 0.0 002 | p1 ros 050 1"0.5 002 | [pres 1 os02| 0.160] p1 ros0.7|10.00 02 | [pros 1 1oco 1 0.002 | : . EN i 1 * 9<0.05 vs. control i . Time {weeks} =Eo -- . ir sH-- RCLT-- -- -- fE r E frpeje) 3 = Aim 3 A re) [Fenofibrate T0710 10.004] pres T 1000 | o.0s| [F1 OS 038 1 0.3 002| eres 1 oso To.0s ] Jrros 1 osos |ose | EEL] fpros 1 1.000] o.15| CT .16 SMO03 Mechaofnfiersenmt FATGoSpe'idcaanmdbaeprroosoen11m66e3als in A0oE3L-CETP mice Figure 43.11 _3 E3 s Plasma CETP mass cFaonraa meareTrorsnes 0 g RN s j8l z 5 a o ` + p<0.0vs5. control Time (weeks) 43.2 plaETsPacmtiviaty IVanliesgaorevsalbuselsuaervgailvueen (ipampople)nadndx1.re means 4 .0. fom 4-7 mice er ru. erm pF ee e-- Fr w a+d a S| rc rH rer el ERs R ros wWof TWY w W|W i Fr-- oma: rBessoo| ounsTT0o01m0]] rm os x pres [lo[T m prereess v110 o o000TTm ox ooomeiam i0 ]| fpros Tosi[ame " p77 M203 Mechanismof diferent PFAST'sGonprpeigdoamn aImeepr0o3t1e55me5t5abolism n ApoE3LCETP mice CFeEnoTfibaracteudeclreevnelssedwepraessaignCiEfiTcPanatlycdyecbeyas5e3d%.ahr fenofibrate and 9FOS treatment. though PRBS, PFHS and BFOS treatment reduced plasma CETP activ, ths was nok hsiagsnisfieceanntnly tdhieffPerTeHnSt ginrotuhpe (PF5BS-1g8r%o,upp=(p=005.21)3.2)P.RAOS tdreecnrdeatsoewdarCdETl?owaercetdlyCEbTyP 2a0ct%i.vity Figure 43.12 Plasma CETP activity s = a0 :Ei x . | zm `uaFCroaenatnrsool s arrrioss Co 10 2 10 i 2 | a 50 rs ' SE 0 fA HH : |g 4 Time (weeks) = p<0.05 vs. contr 4343 Tn vivo cleaorfaautonlocgoeus HOL VEnailrueosslasreroarteelvaoatfilvHueeLv)a(lpuooetnss(aH%raOoafUinnfjsoerctr=eadc5di.0oa,srearlfoocmopa3lbaaisnmceardpaeteceaoryfooHufD:lLabnaenlddehdmdahautloHlvoDaglLouuessfoHarOreL) Given n appendix XI. 7 ss ro sR me ena [Fenofibrate vs. P Er E eE e levis lpres T0016| 000s | ooos |ooos | o.o0s | 1 i000T0310 | ooos | ooos | o.oo | Jpros 10222 T""o.008 | 0.008 | o.008| 0.008 | fpros 1" 0033 o0ss 1 0.008 T0008| 0.008 | p [; eor seree m[] rTerm] fET Eae o = Or T] sd) 003 [Fenofibratevs. [[-- Pprerssoo 1 o0.00s s || ----: sdf [Fenofibrate |G06 | d a a = E 2i WW i eE C=e =a]=m El L , p79 M03. Mechanism of diferent 5'Tso rpeicd annudmIbpeprr0o3tsen13m68e5tab n APOE3LCETP mice Figure 43.132 [*H]-cholesteryl oleyl ether decay in plasma 100 A . . 53 Ne iz3 A ii Es 10 2 "N econnctees pres r~PoFHsS * 8 Ww! | : 10 2 BY Time after injection (h) *<0.05 vs. contra Figure 4.3.13 08 2a3 gooss 23 11552%0032 E ot Fractional catabolic rate of HOL npyd . gins si Br rn a=FCaonnortlbrae aprFvrBeoSss . 0.0 . + p<0.05 vs. control p80 31903 Mechamof arent PASp' 0r9 3ned pstrtnymetabo in ApoESL-CmEiTcs Figure 43.136 Cataboll rate of OL os waetts vs o apHroreeo]s 2_o4 $i3208 FH5%do 01 pic 00 i +5005 v. cont 4346 Uver microsomal DOAT activity Voaluuesarr aobouatovaeluewss(omohl miagpnraotein andar means 50. fom mic per [[ = peu armpmose o a]e [2] 7] f= a= e] 3 SI E II 3 mm [Fenofibrate10.841 0.05 | FEIf E --e eL me m] m _ fpros 10.01611.000 | P frros1001s T00s 56 | p81 3MP03 Mechanismof diferent PEAST'HsOonpropjiedctannudmpbceprro0t3e1i1n2m6e6t5abolismin AOESLCETP mica HeSehrpoa)wteiwdcamasitcsriregonnsidofimtcaoalwntalDryGdsAInTsc-gr2enafascketadinviicnteyth(IenwhaPiFgcOnSietrprreDaiGtmAmaTern.yt2iosnrcvoiauvvpte(ydbyi(n54V7L+5D7%L3)%.a,sFsebenmeobfl0i.yb0r5ia6nt)e.the $73 and PHS showed no Sgneant eects Nt$=ho0en.eI0v5oe6fr))t.hSgtnrkeaantmteyn,t gSrtohuopusGhafPeFctOeSdsDhGoAwTe-d15atcrteinvdet(opnrairmcasriSlygniinivcaavnecde i(n+T5G3%s,torage in DPFGBAST-t1renatdedDmGiAcT.-2 actives tended tobe higher in the PFOSgroup as compared to the Figure 43.14 Liver microsomal DGAT activity 5 i.zHicn cf ge sg: Ee ? :sT!I EE 2 CSFoarncenrbrae Saperiess arros x 3 iih Rr 5 0 DGAT-1 DGAT2 + p<0.05 va. contra 4315 Liver lipid analysis VIanlduhesiartevaabstosluatreevgailvueen (ihga/pmpepnrocteXiin.) and are means + 5.0. from 6 mice per group. FPn T:oeemrpae J =w [1 Tw TT~1 FFereram oTo Ts[a2 [a] Fa Mr r EwTTsirTEeTmo [aaT]T] ts smntate SR En rer [TT] prLHe LE f [Eenotibrate10.00410.002 1 0.00210.240 | pres T-o.04iT 0.041 1 0.0261"0240 | [pees 10.24011.000 0.937[0.015] pos 1 o.o261oc0z | 0.007 | 0.002 | [pres Tose Tose105s| 0.695 | pros |" 0.002] 0.002 | 0.002 | 0.002| pros 1 oo02| oooa 1 0002|o.002| - Ep--N - E 2509 upras 3 ~PFHS 3 3 100 2 = os B . ao " p83 SHOE Wah PgS Tp T REET I 1 1as8in (S meeSmmoseroyne0tee.A sPiene)XiA sea t 3werolserNs EawSare,SyEaomiE,ne Tone Tae 4316 Hpathloicaly aminationof tvrs p b e p eo ee s e |er T i Fe R e e e |n ie e) p p p M e e e o o e e St I Ee Te e KAe a mp o ee e o e e e e e ee E p e F Se--e--se e e r e + b] e e e e [-- 0 Il H cSggoo Te I SEa,iESyEJeLe iSv8,LP E]aWoTpeL,23 sp Toooe]domhee ES om oss 5 itn S, igure 43.168 40S stained convo ers Re Hid La ; `- 8 EE miT e t i Tvy aispantonsat pe 803 Mechanism of deren PATSGorn 9esanmdarltpeospr5otein15m0e8tabo n Apo LCE mice TRaFoeenaoeftitromainte.: wTeoofnredeina8tiCaytreoPuyntodpatthaeepCdeaiertraonelesvuptiaedd(ahInuTrefew3pe1rr6ept5re,orteticenaeocen4o.u3as.1n6d)o. pSeMsoo.usseTyh1e6 Shoe odians neptacaar vacsoion Figure 43.165 WPS stained vers, treated with fenofibrate N 3 k @. || ; a8e J 2o o 5&4:: FPDeranewiirnnagtaoefvireesrmtmaaebnnet,((smmhooouvviseng81,0z,1o1n6e0000A0, 85nd (1003) ve cant vein Teihreeasd:Sihoowend oqf PeFS.tohheegadrieotcrheestuteidctInosfaecwaesrorvtosi(nFaocreeou4.d3ro1p6le0tsh. eTre3.e3.o1u0t)of ve Figure 43.16 HPSstained iver, treed with PFBS rl 0 N `- C5i:: PPPrEPo0SsS rrteeessstttmmmeeennn:tt (((mmmooouvsvee 11178, 111000000984) Fa rd x [| - x 3803 Mechanism ofafferent FAST'sGopnriiedtarnudmpooeprro0t3e1i.n3m8e8t5abolisimnAPOEIL-GETP ice eTphmresa:dTdyitpieonrroofDEGHaSndtontaheadiinee,rgerasnutarinCfOeUweNrSpErLotetinoapceeouss,roepilpeetcsalTyhinhzeopnaetocy8teCs Shriougushnsdcrhoevpaaccteuonccala)alilvoaanr.nT(aoToucrvea3c49.iT3oS16Ga0at,REtTaohfeea4S.3e.1rr6).fyoOuve.iCmkoelo.nueoscmr(yo45LS3er)ohwheeopdmsteoodcOaRmteoSndeorvouettys Se Geected nthe ers o3fout of 3 mic Figure 43.164 HPS stained livers, PtreRaEteTdEwTith PFHS aEg x A B AAETRR ACe all hPail 2 oe 15a A BRN eA |} Ca tes vn Skt Rely R RSORPAS E S RLC EI] T R BABNS eAETAR sEe RG anBR RSe RE A5::: FPPFHHHSSS tttrrreeeaaatttmmmeeennnttt (((mmmooouuussseee 223732,,, 21100000046x))). Agoregates of nfammtary cls (orow-s) TsThioeesro:"vaadcdistoiloantoonf ofFOthSe ctoapthee sdie(tlabrleesu4.t3s1d6).in Phuypreertr4o3p.h1ic60he1pawtahccyhesstawiinthingfionfe TPEdGS,faDdEMvSacaunldescoiminreehrespwaatreopauftnreOx Sfo tcrehatmoetnntr, ary 3nowed the ncressed Figure 43.168 PFOS trestmenvtsPFHS treatmevnet control . Sbe E aR aewh Ex od fo R Sm pAe a i S ar e |} ri7 e E p lN hii 2A5: CFporOrsSlttrreeaoattummesenntt4(,(HHo3ou0uss0ee)222,, 110000%0)) " FL) Mo 7. f vii 3 rE w p86 M203 Mechanismofdifferen PETAHS opnropjiedctanmdulmpbaeprr0o3t1e1n26me8t5abolism inABOEDL-CETPmice 43.7 Liver microarray analysis D6vaeirracgemriapcprnroatgrarrloaeuyspaofnTshgieeynasetalenxpdtrresasunsbsicsoreniqpudteaonmate goafennaelelyesecixtsperrdeesppsoiorottnw1sdaaIytnsaclwauindaetldyrsiainnsaswpeapresinppdieioxrnfXfokar.cmteIodnrsatnis V2a0lueGsenceosreincvioelvfeodr(m10udlcehatnegstveed contr, WER 4-OI0ES) ore SHOWR. Qvalues ore Triglyceride metabolism nupi6onTtlesdiw,sitPhtFheS4h.i3gfheardliapnodlytFicOaScti2v.i1tyfionc)plwaasrmea,inhcerpeaatsiecd.mRNA signas for LoL (fenofibrate AFPaiFttHtnSyodaagcnhdiarPimRiaOcjSoerrseirvdeeqeruailsaytGnoutrnheeosfsifsIantttyheacfiadtsyynatchdesissy,ntSheRsEiBsPpAaCtwhawasydwecerreeaIsnecdrewaistehd,PFS, SSieunVgcigrreeaaslsteiAdnGgbSythgPaetFnreSseqaaunnaddtPiDnFGASdToeEswneortetiankcerelaasceed vwiitacfteinvaotfiroantoef,LFRHSbuatiproPbRaObSl.y SviCaDPZXRw.as Table 43168 GWietnheterxapnsrcersispitoinondaftaacotforstraingdlycgeerniedse minevtoalbvoeldism pathway Eero oratr orerr er e Ee a Hehe h s He e Hea a eFeat E er HE rr d EE e se Eee Be mm B EE-- 8 r mm RAim3 prommn3L8f3 ra S ees LuH n [oo P5 RRRLHs3oa5y8CaRE 31 IFeedet [(i F=SEiEEiEEtEnH : SE S=emEiiEdST men 3.12 HI D0 f EB ESe m r os s T Tra ope eboei Tro o rFa o Fee 10rea ar--r ter CEo EE 0a0He0 R T0P 0 eTWn J 1t :1128-- WC--2+-- 3 E3 e aes a a EeErca Zonnio E ea ei hy os x4 Hats chr of irre FiS an ionpn pt stl n AEL.CET ic EEeEFR rerErE E rv FS E FR T PEEep he ie EEe E Ee E BEr D na eC e F Ee BeeEl E E EEna r h e e E e ee Hr R iBeeEe EE e EE rEi meN d gE eE H stayF Haed E eS T y e SEe iiE Ee ee| E e PBhr h e h h hi e rese H T i eee i EEi 1 EF e Eee bEETE e oE eeeee Ta e TCR BRERR orEsoweeo| Ef BE --ra EEE reare ri mH 8 C58| E EEee -- e a na----: -- e ----m-- e a --e] rLe ] e E pB E --t Etn cae tof ty cis (e71s30 1, AoC,seencn etrae, rC CtEace sCpe,aBbrSisneg aketwninading,nmoes p,roFmotsCor3 47, nd T TTiaeree este oe n stal LoL rears 3 0, LR, ws rss +aa 73 chow no efect on ges veg rgcendsErSt cE es ore mi w" no Sus Hechoaft 8STiOsn RapsI e sol inASE CET ie Crtetarot metals wepe recor Ivenntakehof WDeL rnennts snd OL, Lot, was reed teSettAtSaahnend sSeEtasaeegressenrSa70nceAeersSeeestsT33eStAnSEeAasvcreehrawonereTcEsrywiattegce.stsHG,SCCA4O5 reacsestoosr aogoarAorSxEeon ee ci ric ay, a a arastiSoonaty,i SeSsoLdtELesedsSanweieTmBcoEEe3ocme7RsOeSEpngaMrassnosdcnaHsonLreanavoeets noeeoipfaserd +a r shoveed eeftne nwSngPsv08vieed ihn covlessmeo loaHei EcSg oresespsoet Tiabea 4t21n68on whOGeRvnS aetcxnopra esannedr asartsog hsndeSoo ntes Tmentaabdota pty rE :E er r nmmmiEEmTee n | EE CEES iDEN EE TVS RT see TO psa E HeeE e EE er e ---------------- e E E = E e re e m e E e ree em ee--e=-- r --=---- e --------E --B--EE ---- E E E H E e-- eH e--r -- E ma a o p89 SASS Mechamofalrrt 3451.9 id anapngprogsht inAPES ETP ie WoL metabolism jSCmoErEepIsplomn-- LaaEvAiTvtveeH-- sroenhSreeemeasinsaiy.PHStoheaemmdasjoar p6rorcogfpHaDrLti,claesdwaHsOLicmraetsuserdtnb,y TtwohpankaoekaamarnceeaivslovtpdrgnousatakwistohtfhOLtocnhogledsetcaroesetairnsE,TSP3a1c, ywassdescorenaasbedlebyor ipoaeoncoaadrteeiderisHorttsoiHRmoapwJetacvttasseeaivNOeLeYwiAHhoNPesSS.08 m5aFOrmSl.oTnnr(SeecccooonntodoBFrppesohve 7=70 showed fect genes inves i HOL matali, nn wih changed OL Table 43.46 GeomnaecerxmprneosnsifoontdaartsasonfdHsDaLvamsetoabeolissmpathway with eyR Ee E T el T i . e S B pee ERn ba R ie pee B B e ErR rh re EEi Ee t E em eT oo RHRe ReRRe Eie Re RS b E r T EE o t I r T EET n YE E e E e SRn Te e . e ee e E TT r i seeensn ey --e m er e os e m ESeEeRED D e Ee Nn enee ee en Re RE Table 43.460 fGains-- eicekxipareesion dataof ranscripton f-- actors nd safety -- R pm E ee E B EEo rohC oo r r r p h ieT een e r eee s Ta n Te n THe oIERa e E E-- HE er g B EB e E er PRn TreTdoretseeHt H aop R meefo Fe w p.90 M803 Mechanismofdiferent PEATSH'OopnropjedctannudmIbpeorpr0o3te1i.n12m6e8t5abolism In ApOE3L-CETP mice 5 Conclusions and comments mIneaaspupreneddixpaXrXaImeatetrabsle(eixcienpctlufdoerdt,hIenmwihcircoh-atrhreayefdfaetcats) PaFrBeSs,umPmFHaSr,izPeFd.OS an fenofibrate on al dPMaFetBcaShafrrneodimuscmepohdyfspailcoaltsoimgoiacnacolhfolPeexFsptBeerrSiolmeanntds tIrnidgilcyacteeridtehaltevetlhsebydeacbroeuatse2s5i%n apndd 45le%v,elsresapreectcivaeulsye.dThbey `IPnxFcdEraSetaissohenodwgceeldenaenrsaoneecnfeofyeolcftCVoLonDkLgh'eyTndGersaatInandsveoVlLavDenLdd-ICAnECtSraingadlnydcmefriaitddteymraeectdadubctoerldainVssLmpDoeLrx-tceperaprCttDfc3oe6r.pmriPoldFduBcIStnicaorlnesaosesshoIwn eBdoonottemufenfeadcseturrsoetndo,ogdenweelsl.inHvoawlevevderi,n rcehgoulleastteiroonlbymeStRaEbBoPliLsam/cetxackeepst pfloacae odenctrheeasperoitneiSnREleSvPel1,a,whwihcihcwhasI.s iPnFBHSDLhamdetnaoboelfifsecmt, oinn iHnDeL-wcihtohletshteeruonlchaanndgaepdoHAOlLlelveevlesls.. PBS showed no efect on genes Involved PFBS mildy Increased liver weight, but had no effect on ALT and development of hepatosteatoss. aBnadsevdeornsmizReNIAncrseigansaelds) PFBS appears to have mild PPARG-agonistc activity (B-oxidation increased The present cata indicate that PFBS has no increased CVD risk profile. TPMheHecShdaranetdiauscfmerodofmpalpahcsymsaitocolhoifogliPecoFsatlHenSre.oxlpaenridmteingtyscesruipdpeorlteveedlsbbyy ahebpoautti6c 0M%RNanAd l7e5ve%l,s riensdpieccattieveltyh.at the aadcentcdirveistatysreoinsngpilnlyapsrdme,dultcohevedelhVeapLraOetLi-ccTamGusReaNdnAdbsyiVgILnnDaclLrpefaoarrsetLdcPlLlep(a4lp.yr3so-idfsuoclatdni)odwna.csleIaInnrcarlneicaneeseodwf.iVhLDtLh-eTGhiagnhderVLliDpLolCyEti,c AdPloFteOhsSo,ungoshetvaetramaklaejgoperlnaercseegIuvnliaatthoaercotfaiftvftaytaitaocnyidoafcsiydLnXtshRyenstbihusetspipasrt,ohbSwaRabEylByPwLevCria, PiwnXacRsr.edaSseeecvdre,eraassluegdAgeCwsSittihgngePnFetBhsSa,,t SrPeCFgDHu2lSataainnoddn aVDdLGdiADtTLiLoTnG,weIsreneccrreeitaniscoerndeamusaepdtyawkfieotrhamnPdaFnHbSi.enxdpiIlnnagcnraoetfaisofenadtfyohreapctaihtdeisca(cfIcantuctmryuelaaascteiiddonRsyNnotfAhetrsiligeslvyetcloesrgieodftehsCerDin3w6tihtaehnldrievedFru.AcTePId,n odaxenivddealttoioopnmaleenostfsoeffarthteyepxattaeocnsittdesaFtAo(sBCiPPsT.IgbeT,nheissA)CoOcw,chuircrehendc,yrledseusClptoiAtferohtmyhdereaontbhassaeenr,cveatdtihiolonllpatashleya.stis(gaemcnaeetysylic-noCvnootlervniezbdyumtieen Bto+ A acyitransterase) ang ACS were increased with PFHS. PsHtDHrLoSngclsayttarbdoonelgcilrcyeardsaeetcder,eaawnsdeedtchoHenDcLml-aucjdhoeorltehgsaettenreboalIsne(vdaobloovnuetdM-iRn7N5uA%p)tsaiakgnendaolfas pHPDoFLAH-cSh(oarlbeeodsuuttceer7so5lH5eD%s)Ltelrleesvv,eellSssR.-bAByl1tdhowoewurnge.h. rmuepogtsuatlkaetliiko(enlSyRo-ftBha1ep)orAeas1ruelstysnoutfhgePgsXeiRss-taeagdnadnitsoHtOibLcemaacrtteiusvrpiatoytnisoi(2bn4l)e(.ABfIoCnraclrt,ehaeLsCeAdfTo)rr.meamTtohidoeenllianotgfte(lPaaLrdTgvePer)rsaHenDdcLhdapenacgrreteisaclsaeersde hPiHstSoloIgniccarleamseeadsuirveesr.weight, ALT, and resulted In hepatosteatosis as observed by biochemical and iBinnaccsrreeedaasseeoddn,; FMFAARNusApynttashkieesginsaI.lnscirnePcaFrseHeadSs,edhvaasenrdstsHriozDenLg insPcyPrnAetRahGse-esdia)sgonaainnsddtcPmXa(Rtl-upaarglaoytsniiiossntcidnecacrcreteaiasvesitdey,d,(oFAxI.viedru.apttisaiokznee increased). " pot M203 Mechanismofdifferent PFA"ST'NsOopnrojpeicdtannudlmpboeprr0o3e1i.n1m2e6t8a5bolism nApoE3L-CETPmice MPAeOsciSmhialrnaeridumscemecdohfapnlaiacsstmmiaoonfchoaofcltePisFotneOrSIoslacatnidvetrwiigtlhycPerFiOdSe lae5vewlisthbyPFaHbSo.ut 65% and 70%, respectively. TdrheecderuecdaeasdteaVsLfiDnrLopImiTdGphalyesnvideollVsoLgDaiLrc-eaplacraetuxispceeidreibpmyreonIdtunscctriseouanps.epdoIrnItpeIadnlyesbiywsithahenpdtahtecilcehaimrgahRneNrceAipofolleVvyeLtlDcsLa-icTtnGidv,iictaaytneIdntsphtlaratosnmtgahl,ey the hepatic mANA signal for LPL (2.1+old) was Increased. APdloFteOhsSo,ungsohetvaetramaklaejgoperlnaercseegIuvnliaatthoearctfoiafvayftaitaotcnyidaofcsiyLdnXtshRyenstbihusetspipasrt,ohbSwaRabEylByPwLevCira, PwIXnacRsr.edaSesecevdre,eraassluegdAgeCwsSittihgnegFnBetsSh,,a SrPeCFgDuSZlataainnoddn DVInLGcDArLTe-aITseGwdesrueecprteaItkniceorneaanmsdaedybiwfniodtrihmngPaFonOfSe.fxaprlItanncaarcteiiadossnedf(oirhnectprhaeetaisacecdcfuammtRtuylNaAatciilodenvoseflysnttohrfeisgCilyDsc3et6roigdaeentsdhIenrFAtTwhiPt,hIvaernre.dduAtcolesdao lhaecesipsdaestro(setCxePtaTetInobts,iFsA.ACBTOPh,igseennoeocycslu)rrwCehodiA,chdheyrsdeprsiauttleatsfteh,reomtohbiesonelhrasaveantc(ieoadncelttihypaoltl-yCsgioesennmezsayymIencvoAonltvarecidybluIttnreafnt-soofxediredaavsteeil)oonapnomfdenfAtatCtoSyf Were increased with PFHS. PCSoFaduOiaSnlgeinfneocrrsetyahnsetehdmaasMjeoRraNnArdatelc-ehlvoielmleissttieonrfgoltehneezstycemhreioflieicsnattetirhooenl bgiseyennetashceiAsdiCzsAiyTnnLtgheeatninczdypmAaeCtsAhTw2aH.yM,GMCCoYrOPeA7ovaesiry,,ntahntadhseeggeeannneeds ichnovloelsvteedrolinmebtilaabiorlyiscmholaensdteerxolcreetxicornetmioany, fAoBrCmgSan/ge8xplwaenraetiodnecfroeraIsnecdrebaysedPFhOeSp.atiIcnhcihboilteisotneroolf levels found with PFOS. PHdeFDcOLrSecaasstteardbo,onlgwilcye rdcaeotcnercealaunsddeedtthhHeaDtLm-abcjahosoreldegseotnenreomlIRnN(vaoAlbvoseuidtgn-Ian6ls5u%pP)tFaOkaSendroefadpHuoDcLAe-Lsch(HoaDlbLeosutlteevr-eol8ls0e%bs)yteldreosv,wenlS-sR.re-AgBlu1tlhawoteuirgoehn. orefsupltoolf PXsRy-natghoensiisstiacndacHtDuLtym(a2t4u)ration (LCA). The later adverse changes are most ely the PacFcOuSmuilnactrieoans,eda5liovbersewreviegdhtb,yALbTi,ocahenmdicraelsualnteddhiinstpolroogniocaulncmeedashuerpeatsosteatosis and iver cholesterol BIInnaccsrreeedaasseeoddn,, FMFAAANuSApytnatskhieegsniaIslnscirnePcaFrsOeeaSds,edhlaiasvnerdstsHirzoDen.Lg InSPcyPrnAetRahose-esadig)sonaiasnntddicPmXa(Rtl-uparogaloytsniiiossntcidnecacrcretaeisavesidtey,d,(BF-IAovxeiurdpattsaiikozene Increased. IlInimpvoootpvlrevometeemnientntmoeftoCafAbRooltaihnsedrm LbXnyRucPilFneHatSrheatncrhdaannPsgFceOrsiSp.ItniolnidfaacntdorlsipoIpnrottehine regulation metabolism of lipid caused by and PFHS amTenhtdeabaPotRltOiseSm.gceannCenAsoRtwhebarese,fbuelhleoywneesvxechlrou,wdneIdnt,corbdeauestcerdseaIsenestshge-loipkxerileyd.saetnLotintexgtpeenIrseiskmenanostwsC.PaTbIouatntdheencroylleCoofAChAyRdraintalsiep.id LdeexXcpRreeraiinsmceerdne,tassheoaswedvfeaectrrte.yasIaencaidnddCistEyiTnoPtnh,eacsXtiRisv.itbyiynwduaIcsnedsfuocuetnxidpo.rnesIotsficoanSnRnooEftBCPbEieTCPexemcxRlpuNrdeAes,dsiwtohnha,etretwhahisiscIIhsn ctwahauessepdr2efsboeyindta SCtbrtaearnxnonasnorcgtorlitypbetnediaeoecn(xr2fce5ala)custdeloederdsa,dascksectieonpcPotePpoAprRRoSsXpi,RoteoPfXeo.ffrofmreascntCdsaEwLhiXtetRrtha.enIsrHfnooecdwrri,eemvaeseIrerndv,tooldlegivvereetelmchseteonrfatcwttioirtfvihagtlRiy3XcoenRlraiodrIfnegseRrtXahRnen,dufomoabbpseoeiBrrn-vscoetofdanntncaeuefidfniweieicnattgrhs UtClrsihapianonnspggcrreotitsphetieIinnosmnio(c2tf5aeh)cre.toroarrmsreat(yAarbHdoa)ltcavbapalrsvoec,eedswsieenssthuaegngdmeespttaatbthaowlaisytsusmdyoIfktexheengolibunicovotosilecvsemmeIentnamtboorlofiestmeh,aelIlanbfioltvaemhmaartenisdopneocttahnetdor Immuneresponse. 0 p.92 M803 Mechanismofdiferent PETANS'OopnrlojiedctannudmIbpeorpr0o3te1l.n12m6e8t5abolism inApOE3L-CETP mice rFMeeesnpcoefhcitabinrvaeiltsye.mTrohfedeaudcctaeitdoanpfolfraofsmemnapohfycishiboorllaeotsgetiecraollexapnedrimternitgslycseurpipdeortleedvelbsy hbeypataibcouMtRN4A0%levealnsdInd7ic0a%t,e aTtchGtaitvaintthdye VidnLeDcpLrl-eaCasEsm,eas,dientshppieitedhetplhaeevteilIcsncMarrReeaNscAeadussVieLgdnDablLyTfGsotrrpoLrnPogLdluyc(ti4i.no6c-nrfeoralasdtee).d wlIainpsollyiisnniescrwaeiantshdedtc.hleeLarOhaiLngRcheemroRfliNVpAoLlDytLai-sc SmIeanvcrerkreeaarlsefdAoCwSiItnhcgrfeeenanseoesfdibaurnpadttea,kDewGohAfeTVrILeaDmsLRDNrGAeA,mTn2aInnatvcotpliavvreittdyciipenrsifwmaatatsryyeanrchedasnpocanensddibbltyeri1fg.oir5yc-VefLroiDldLe sseycnrtehteisoins,tewnedreed m(gtoaeocnsbeetetsypIlirn-nocCvmrooieleanvnseezendydtmlibeynyCBA7-Do33axc%6iydla(attpnri=ado0nn.s0Ffo5Aef6Tr)Paf.s,aet)taIynnadanacddtidodisAtaiC(oSnCl,PeTswgs1eeearrneeaesnxstdtiernon1vntbog,llFvyAAedCBIO?ni,cnrgefeeananscteeyysdlawcCweiiodrtAehuhpIfytnedacnrrokaefetaisbaaersndae.td,e.btSiheTnivdaoeilkrnaedgsn|,e fteongoeftihberratteheonnevteerftfreicgloyfcetrhiedeselecvhelasn.ges In metabolic pathways In fatty metabolism Is no effect of awIchncicecolhnecrlamutaseiydon,pbeefreinpcohafeuirsbareladteLbppLya-rmaeednodhxiaiacntaceledldy liihnpeocplrayestaiisscesoffVrLeVeDLLDfIaLTtGtyoprraocbddyuctuIinpoctnraedkaeesspeidretseduelrteidnnugocvionfgrohpmelpaassttmiraconTgTGlG,y Synthesis. alFenevndeolfsdiebocrfratecehaoslreeedsdtuemcrReoldNAslyivnleterhveeclthsiocloefestncezhryaollmsetcseorn(otHleMntGmeCrtoeasAbuallstiyiznnigtnhgianseeennzahynamdnecsr.eedd(uCcLYtDPaL7sRaedm)a,nRdNtAhseqluleaavlteetlensrealsneydandtimhnRagsNetA)o Feduced fecal bile acid excretion. AeFlfeftnehocoftuiogrnhatatephoeiAnlmc.arjeoasredgeHnOeL-IcnhvoollevsetderIonlup(t+a5k0e%)of aHnDdL-fcohromlaetsitoenrolofelsatrergse,HSDRL--B11,pawrtaiscledse,craenadsehda,dtnhoe cPwaPatAsaRbGfo,olyuc-nadrgaotmneaijswotarssly(n1a4rt,e2s6sp)iog.nnsiifbilcaentfloyr dtehcereaisnecdr.easFeednoHfiDbLralteevesltsrounpgloyn dterceraetamseentInwCiEtThPfeacntoifviibtrya,tewhaincdh cFheonloefsitberraotle cionnctreenta,sed liver weight, withouteffects on ALT and hepatosteatoss, and decreased Iver uBpatsaekde oinncrmeRasNeAd, sBi-gonxaildsatfieonnofiinbcrraetaesehda;sHsDtLrornegmoPdPeAlRiGn-gagdoencirsetasiecd)a.ctivity (Ipolysis increased, FA a p.93 3203 Mechanismofdiferent PRAST'NsoO proljiedctaundmbpoeprro0t3e1i.n12m6e8t5abolism i AOE3LCETP mice 6 References 1. VLdeaeirndeBdneonogemMnaeaH,gedxHehanivbbeekrhegyspAerMLiMMi,p,opFrHrooatfnektiesnreRmMRiK.a,.TKrJraiBnimsopgleenCnfhiocertrmPi1Ic9Ae9,3c;daer2r6By8ri:unigj1n0t15hG4e,0-va1ap0on5l4iVp5jo.pmreotnei8n, va3n- 2. IFVnraaannptoVsliijRpRmo,pernoHto8ef,iknevraE3nM-HdL,eeinHdaeMnvoeatkgredasnesnLgbMee.nriDcgimeAitcM-eiM.n,d)ucCGeiidnbehIlynspveeMrs3lt)p,1o9pv9ra4on;ted9ie3nr:emB1io4ao03ma-n1Hd4,1a0tHh.oegreonscElsecrhosiHs, 3. mHGriaocvoeetkeaPnsHdEL,iI.tsvQarunealnatVtiiitojanmtseihnviep BtaIosNs,sesesBrmeuenmnstocnhooflGeHasot,retrioHclofaketxehperorsoMusrHce,l.erSocAshriitsfefrIeinloesarcpsloerER,3TLheViriddoegmnebontVr-aaHsnacsr.gteBniMio,cl 4. iHK1tai9s9vep6eal;kmaeas1sn6mn:aLM9R,c2,h6oRP-lor9esi3sunt3vce.aersnotla-HtltGionw,eorreiEdnmrguecieeyfssfe3ac,ttheIJrnuoskacpelomeEar+o3sJiLWseidFdeoevnnetljtonrpaRmnDes,gnetnHibocerrymeoivncodee:tasnEdvAiIidGne,dnecKpeoeanfsdoternaatntioT-,f 5. NDIeGlns.infgDifDflIeMr,eanetJfiumafkleecmemtfsafoeacfJtWsoo,sfuvvaaanmstldaoetdiiWnpi.ienleCiMacAnu,ldaEatmtieoorinvsa2s30t,0a3tv;iann1t08dr:eerat1Lm3oe6an8rt-s1ea3n7Ad,4.tHhaevierkceosmbLiMn,atPiroinncoenn 6. Va7te0hresrcohsucrleernosLi,s In ApoE+3-Leiden transgenic mice. Kleemann R, Offerman EH, Szalal J Cardiovasc AJ, Emels 33, Pharmacol 2003; 42: 63Princen HMG, Koolstra T. lmEefisfcieoecnt"ArotfeprlriooowgsrcdleoesrssieTohnartoormvabansdVtaa_tsieinnBflvolelarms2mu0as0t5id;oine2t5-:in1ind7u_.ceadpoclhioploepsrtoetreoilnloweEr+i3n-gLeoindeanthertorsacnlsegreontiicc 7. GpDelelasstimnagEClDMiI,dMs,BlbPoyokssItnhVSiWMbi,,tinKGgurioVpeLenrDesLndFp,irkoHdauHcMv,teikSoeonslaaaLnsid Kea,nnhdvaanPncridinengcreBhnoeopHmaMtGaH.b,ilvRaaorsnyuDvupaysdvteanteivxncoroerrtedideouncWeI,sn 8. `FKAeonpoookfEti3rb-arLaeTt,eidVerenerdsmucichceuesr.e)antChaL,rrdovigaoenvnaesdsceirsPhWaeinlr)mAaJcP,oOlEK*o2e30nL0ie5gi;dWe4,n5:Tmo5i3ec-te6:0K.,ePvriidnecnecne HfWoGr,muKllteieplmeananntRi.: 5. a2t0h0e6r;og2e6:nic232ef2f-e2c3ts30.besides. lowering Van Vijmen BW, Mensink RP, van t plasma. Hof HB, cholesterol Offermans Arterioscler RFG, Hofker Thromb Vase. MH, Havekes Biol Li. 10. MeEEf3*lf33se,-icLtnVesgoainfdDedIndiMee,trtraaOLrnfaysfagreiesrsnemihcaAonl,mliEcJoeNun.,ksevJemaLraniupmiJDdWul,RypevisHedsan1vva9eobn9koed8er;sdVe3L9LD:MWL,,1k1Pivr8nai1ennt-ci1ced1sne8r8iH.nBGhoy.opemrTlhHie,pidadceeymliW-ciCtaopREocClhHio,ploepGsritofetbreeoillns 11. cVachoyolllgteersratneOsrLfo,elr-valsaoenw.edrei(rnAgCBAeoTfo)fe-mcitnH,hinbadieptooWrEi_t*a3vELaCesMli,dmeivnanmicDreue.yduvCceienrscu.uoloaarttidhoeenroW2s,0c0lHe1ro;oms1si0sr3:aa1dGd7,i7tP8il-oa1nta7lJ8,l6yH.avtoe.ketss. BLSleMoc,lre2tM0ie0on1nd;ian2nk1d: Rb1Pi0,s46s-Pa1rt0iu5nr2ca.etnionHMIGn.3p0DEi*et3aLrayideplnanttransstgaennic emsitceer.s Arrteedruicoescl\eLrDLT-hcrhoolmebstVearsolc 12. APZrratidenerclieaonascrHleMAr,STMhK,oroolKmsltbereaVmaTas.ncnBMiooRl,us2Ve0e0r7ms;ochd2ue7r:len1f7o0Lr,6a-td1he7e2rV1orsiceesr-ovsains daenrdWpehlajrm3a,cevuatnicdaelrmoHdoifoiemrs.J, 13. W`HaeagsvgterekarvetasetreLpsM,Mat,hReVeranonssecdlneerrPoCHsNio.sogiCtnhoAClCPe,OstEdeer3yLHlealeadsnetneWr,mtiOcreaf.nfsefArormrtaepnrriooEtsHec,ilneDradTleihcnrrgoeaam-sbTehsViaeHsGDcHLB,oalJnud2k0es0em6va;erJ2eWl6,y 14. VP2ra8i5nn2c-de2en5r5H5HH.oGo,gtJCuCk, edeJWH,aaHnavWe,keWsesLtMe,rtRearpseMn, PHCoNe.kstFernaafMl,orDaatlelInngcar-eTansiees GHMD,L RchoomliejsnteJrAa, 15. bbDRyoyemrriHeejaddnauunccJiiAWnn,g,gJcCvuhEakonTleePmdsateeerxrJpyNWrlo,eoesgssHttiaeovrCneCtk,irenaWsnceshsfLoetMlre,erspttRreeoerrtnopeslie-,nfneedxHPpoCAreNePk.sOssEtiA*ort3nao.-rLvMae,JsiLtDdapaetilnidlnCnRgEieaTns-cPTr2he0mia0ies7ce;eGs.M4H,8AD:tPhLre1irc7noh6cso3ecln-lee1sHrt7oMe7srG1ia,sl 16. VP2ra0i0nn8c;dene1r9H7Mo:Go5.7m-N6i3Ja.cWiAn, IndcereaHsaeas.n HWDL,. BbeyrbreeducJiFPn,g hHeapvaetkiecsexLpMr,esJsuioknemaandJWp,lasRmeanselenvelPsCNo,f 2 p94 3M#03 Mechanismofdiferent PFA"ST'NsOapnrojpeicdtanndumlbieporpr0o3te1i1n2m6e8t5abolism InAPOE3L-CETPmice cBhioolle2s0t0e8ry}l 2e8s:te2r01t6r-a2n0s2f2e.r protein In APOE*3-Leiden.CETP mice. Arterioscler Thromb Vasc 17. DWdeoesetsHearnatonetrpWr,eMd,udceReoVmaritijnenesr-JovAsa,cneJrduoeksreismWaelb)JeWy3,o,nHvdaavanteokdreevrsasHLtMao,timPnriaJnnWcdAen,InHGdIauGuct,eiseRremnoTs,reevnapnPrCodN-e.irnTfoHlroacomegmttartaCopCrl,yh 18. lPdeeosfsiitocniSseMn,tchyaGnrinoaetmonirecvnaedsitoakntiHnMa.,nCSioarlpcaouaElsa*t3Ki{,oeniRd2ee0n0ns8e;nba1Pc1Ck7Ng:,ro2uP5rn1id5n-c2ie5mn2p2aH.iGrs. veCrhyolleoswt-edreonls7iat-yhyldproopxryoltaesien 19. pDru1oi,dvueNcnitveioounow.rednAehrunteirzI,ieonVsocsWlehFro.lThDPir,eotmaRrbeynVsasepsnhciPnBiCgooNll,i2pD0d0us4y;vleo2nw3v:eoro7pr6l8d.ae7s7mW4a,. cRhoomliejsnterJoAl, Eamnedltsri3a),cylHgalvyeckeersol. 20. aPexoncsdrteptSriMeo,vnendItenlCterrvoearnmssgRte,enaivtcoasnimsiHcIanepaeprwoieEtnh*R3,eLleveiavdanetnTeodmliecAxe,p.raAensdmsiPJornCilniconefnNuhKtuMrm.a20nI0n6cp;rheoa8s4sp:ehdo3l1fi2ep-cia3ld21b.tireanascfiedr 21. pKHreionetdeeriminak.nAsrntHeF,r,ioZVsaecrdlseecirhTaurhrreSno,mLSb,miVvtaahnseGE)Br,kolKMa2)z0,n03Na;ickho2el3s:eky8V9,Y2,h-i8Ck9ro7ul.sbkbaeyna TN,H,MeVlenrihkeolv AE,R,HuSrmti-lCaemeAlK,d I`E,mnedtvuacabenodldoembriycGsrIaennecaflryesJa,isse.vdaGnedinOeotmmamreyeBnoclh8o,2l0es0Kto7ec;rios8lt:raRI2nT0t.a.kAe:ther3osccloemrboisniesd.andtraInvsecrrpItnofmilcasm.matainodn 22. Hp3a1or9vti8ea7kl;elys2a4Lv7Ma:,ia7db3el9e-W7if4ot6r.EdCowan-nrdegPurliantcieonnHoMf.loCwe-lelnisairtyfr-eIepocphroolteestienrorlecienptHoerpacGt2ivkcya.llsBisocohnleym. 25. dMHeCen,nssivteaynnklaVpomipjprmoAetRne,in8v)a,fnoHrLamuavytenikoeMnsJ,aLnvMd,anaKpGuooilpoierprospH,rFo.tBelHioenkpsaEtV,idceApplooissidtteialocFnc,uimnGurlaeapetovileiopnJo,,praHolottfeekirenerdEMv3H-e,LreyJiodlneognw 26. tDLriea,nHsPagraeinnniccWe,miHdcMee.GV,rJiHReeespn-asvtaeonnldP2eC0rN0.W0ePAlXu)gR,;aMg3o3ol:niI1sM8m,9-dH9e8oc.crkesatsreas,HORLomliejvenlsJAi,nAJPuOkEema3-JLWe,ideHanveCkEeTs?. 25. dvmPeeriircVneycr.eilneBoslwH-o-vHcdah,eninmRsdioeBtriymoWiplehiyJipAso,pJAr,cSottdmeaeiitn2HJ0apW0ar9,no;dRWu1e,c7nt9siH1eou,nnL1F,a9Cn.1K-du1iB9fce7hxM.oa,lreoOstteeernHyeLl,inevdsautnceerdsetdrryasHnlosiofperirndepJmrWio,ateHblyanv-iemnkecedrsieaatLseHed,d 26. VarHteaMhdnGeur.codtseicroTlnheoHrefoohsoiidsg,uhaI-nlJduAePknPOePsEmAtaRy3o-lJ/lLWype,oiprdHaogeatoenvine.ni.kCseEtsTEndtLtroeMacs,nrasigLgniueotnnlaidozchgayromii2cm0eb.0lE9o,c;BkiCs1ta50mJp:ePrhoo2ag3rr6Gme8,sa-sc7Rio5oel.nns2e0o0nf9;PCp1Nr5e,6-:ePxri1is0nt6ci7en-ng 1075, 0 p95 3803 Mechaofndiifesrenmt PFAST'sHonrleicdanndumpbreort0e33in13m6e5t5abols in AGGEIL-CETP mice 7 Appendices Appendix Bodyweight Studvi [= =Per e e r e ESe e e r 2e C ee ee] E 5 T a LsT2T1 ess T21 901 260| 290] | = 1 312 TT 230 Tosa 1 264 1 266 | er e T TaeTosTasT30 ] T T r TT e S T e eT3 e se TTehee]|| E e| i e | 6 e Te o s msTe see a a] g Er T T rr S ree | [E H 2T0T oeT ToT Te o oTasaJ oo [a7 aese e [o2 odeas| oo26e0 || r ET r roJ rr wr0OY FeToToh ToTos or os oa | E e eS E 5 5 ESIe SS CBo {3 ToTo . 1725s [9s |208 | 26| 2| 8 To ree e TTee sTae eei Toae s fo eTro T e rerTee eee e Treea Ta e | F F ea e e eee a aea] Week's: morm 1 as TTni se-- parate Co-- s (100) -- Beis-- of Ting wounds P p.% 3103 Mechanismofdiferent PFAST'NsOonpropjiedctannudlmpboerro0t3e1i.n1m2e6t5abolism in APOE3L-CETP mice Stud2y [= To E S S m e cr em]| = = = e emee T rTe e T S = T SSr S BS e s e e e 2 a e| F T o r h r e e e ] e o E e re re s ee s e a reee | s T T i] E FF F S e Se B--e e --ei ee Te e 2--ey t o F om e ei Te ET E e n e Te J se JT 5 s | = B e o sT h r ae e a Te E& e r a r r e e i an) o e r T e e oe ee e|| S e o r e e e e ] e ee T T r ie a p.o7 M203 Mechanism of different PFTASN'sOopnropjiedctanndumlbpeorpr0o3t1i.n1m2e6t8abolism inApOE3L-CETPmice Studv2 r -- e -- rmr r -- --m e F Etre e 1 Tr sJa e Er SS r T Tr E ---- T oT e er e r hs T TTT T rr ] eee F F F er T e r Teee s V TTT R r Te| F eT er rer e wea Ts| E FTer RS rRe TRe Y Y RS ea| o i T T ee Te eeT e w T r T T TeT Ti -- r F I T T e BB rr 1e Tie ne eia ae e e F i e o heee e a] E' -- -- T re 1 er a1 y gr TvT eee T--reear --1 o re e Toe ae Tee ne e r rr r e r r % .sB 3203. Mechanismofdfeent EATSGapn Iepcaandmbpeoprrootoen17m6e0t3abolism in AsoE3LCETP ice AppendiIxI Tissue weight states Body weigh, Iver weight and perigonadl ft weight at sacrifice F a e e F He t EE e i a e + 1n a n 1 -- || 1, a | i t A a r 11a a sn 1. es|| a e F a et a i---- a F ee s a a -- r 1 nm | :E --F r -- a r a e i E = EE EE + 1i in | T fs J 2 ee -- PB p98 3M#03 Mechanismofdiferent FAST'HsOonproljiedctannudmpboeprr0o3t4.en12m6e8t5abolism in AGGE3L-CETP mice Stud2y Body weigh, Iver weight and perigonadal fat weght at sacrifice [o- o[F e To e emee t e 9 T e = F a T h n e 1 T T| T r T re f f = r e e i F r r r e 1e e ------ F = fr e| .S Ft r oi|| a r or a eg H rr r re | Fa E e e r e 7a e| -- E F ree en ss p.100 3403 Mechanismofdierent FFATSH'Oopn prd aonnudmjIbpeorper0o3t1ci1n2m6te8t5abolism in ACGE3L-CETP mice stugea Body weigh, iver weight and perigonadal ft weight at sacrifice. ETEae l E lleo e r ilrl, lll ==e a Bi E F E F a e e e ---- e Fo ------e een e rr] i --T-- EF e ES ESEeT R eeA e e eTr | E E e e e ee -- EF= e r -- ---- 3-- -- 1|-- | E e e ee s -- EF E E i e t s 1 i=1 u ] dSems + zm o o E F rtea ] e e eeee -- = e F 1 e 1 Jes | 5 p.101 M803 Mechanism of ferent PFTASN'sOopnrojpeicdtannudlmibpeorpr0ot3e1i.n1me2t6a5bolism inApoE3L-CETPmice Appendix III Food Intake Studsy FoTodTnDae r e re a e ] T T -- --o e -- | -- ---- -- n -- -- ] --1 a T ao --T w 1 --s--o 1| n --a yr-- T --Ta -- a-- s] e --e c--e ---- r [or =T7e e are aT] e ES -- -- TeT-- a i--e]| e 1 e eeTos] oe rbroteey -- C-- S-- 0 c -- o o-- s o-- e | Eo I C J 3 0s || T -- or -- X T i ---- e o: iT--oo e] S o o --T-- 5 esseT iTT-- eo e rea e || Ee 1 ToiToo. Ca ce Tee ro eTo o oe Tos esTei--] * Wee: mouse 22 put in separatecage (10), becaofuisghet wounds 100 us sT3Ec 5 mser n in a E E e o 2 E r s s a SE he Re) Ee E ees) E EE F E Ee Ee e e s= ] e = og Y | -- r= IEE ey E --E-- ST---- --E=--s ee esiS , i e e 1 r r de 7Teas i [SE S=tu=d3y E=2e ==5=]| E Ss E SE E eIeET Ee eEe e =e e =Ee e] == Cs 10 T-- 3/1] [7 = Pe Pare .-a .Sy 8 E E E ----e E E ------ [ TT a 2 e TT ase t E e E E E E1 =e E e E T e oE E e eTe E e E 2661 . E E -- ESSE=S-- E =Se =S=E-- E ==oS p.104 3803 Mechanismofdiferent PEAST'HsOonpropjiedctannudmlbpeorpr0o3t1ei.n12m6e8t5abolism in ApoE3L-CETP mice Appendix1V Plasma cholesterol Study1: om mmosee smmn T [T T e we T eonm eeee E= E eeSOTe ee r Tes e | Ee S e e e Te 7] T Te e| E= s T Toer s J se]| Eo T A S Sr J Se B e S e B eeS ] a|| E e e ae S e ---- a ee Te ose Tie | ee ee > J TR oeT ec e a S STT --es nCo || [= ow 0ToTs e a es] s r oe o e r T ee e ] r se] T7 e T e r T T Tee Te T ee e e Se a e e) Ee S T Te s oTT T oToi e e -- e a -- a ] --e T--eae] e E o e nTe r o Te e e eT e ] T a e s o s Te ee e ase e Te ae e e oe e ee e ee a ae e T | I --TT eTee5)----ie] 103 p.105 3H8E3 Mechsofdiferent oAhS oen peid smnamptaapain58m8e8tals ApGESLCETP ic Stuy2: IIF F e I eeest e a e 7 | F rr I. F 1 F 1 C E -- ------ n ------ -- = F Fa r r F-- F -- a ---- -- ---- -- t re -- e -- -- = -- E F e | T FF i o t o s e ----oe-- s] e. F F ---- t a| SE E E------ ---- -- 1-- 10s p.106 3203. Mechanismof diferent PPAST'sHornepicdtannudmIbpearp0r3t4.ei17m6e8t5abolsm n APOEJL-CETP mice Study: I= F lrllee a 1 = = r 1 7+m--|| T = = a a-------- ---- ---- -- a oe oa ipeess--s--] F = H r r a +r e H r a -- ---- -- e E e hy H e i" -- ---- -- F -- Ee n e --= --|a Ft o es n ne-- E F F E o + o t + e| r -- 10s p.107 M803 Mechanism ofdiferent PFAST'NsOonproljiedctanndumlbpeorpr0o3t1e.n12m6e8t5abolism in ApoE3L-CETPmice Appendix V Plasma HDL-cholesterol Stug1e [oo [= |oo P TS ro te]| TeT e TeTe F T r ew es ome Te ee | S = e ---- eeee e e e -- e e e -- ] ] -- ee--T-- en---- en F F FeT r e Te e T eT T e e e e aaaeee pe F Ter Tre e [Tr oe we Tae no] e [e uame | T e re e T s a ] F e ees r ee e s t n o e e e n Te e Tro se ee] e eee en ee T | --e ES-- I"S---- a CS --ea oh] ---- F onT e -- sTToee] 108 p.108 3203 Mechanism ofdiferentPFAST'HsOonpropjedctaundmblpeorpr0o3t1ei.n12m6e8t5abolism in APOE3L-CETP mice Study2: [To | oo [ov [e smno cT me m. n] To Tn T TTT reT Toon r o re T T TT ] e -- r e rT n o T a ey-- e e e -- T ---- eT e s-- e -- a -- T e r r see e T eT Te Te -- e -- ae | -- --T -- os-- T--on--] Ee S J SS a BSI -- Ee E T--T-- oT --e -- -- e T-- os w-- oTTo e Ta o e s vT eo n e T r so e r e To eeT o Tes -- ---- TT sa ow] 107 p.108 IMP03 Mechanismof ferent PTEAHSOpornoljedctanndumpeoprrotei031m.e12t6a8bolism In ApOE3L-CETP mice Study3: [oF } ooPI opT e ---- pe T 7e, --| T r Te r e e r e a e F T r T e e e r T s hr e en e F r F r t w T ee)| Fr r T re r es rT ae B T TTr e Tee os p=) F e F e r er Tr eT r t we eo e r ns r r F rte r r T 1s T T r TeTee T m Tea e en e F e T TTa eT Te eT T T y g e n Te ] en a| o F r TTs r r a t 1on --] -- F a ee Et E -- ----[r 1---- -- 108 p.110 3203 Mechanismofdiferent PETNAOSop'nropjedctannudmIbpeorpr0o3te1i.n12m6e8t5abolism in ApoE3L-CETP mice AppendiVxI Plasmatriglycerides Studay e C eC e Xo E E EE E t ES tS e Er E SE J Jrr e JRO r re Fo E e ee e r e e 52]| r -- oe -- e -- e 1r 1s ] s] Eo F Y rn e e e] 1 | EE BB e S 1 | r re v e r e Se R ] ee | I e ------ ------------ ES e| r oe Te eos r Te re t o F ES ee -- a O EE C 1| eE yT C --+ ree r Rs S] 1 -- | 109 p11 3803 Mechanismof diferent FAST'oopnrpiedcannudmabeprr03ess13m6t6a5bolsmin ADOEIL-CETP mice Stude2 [oo [oe|eee) = FFT e ee = = T T e r T T i] oy ------e ------| fy -- e -------- -- 1 --r ------ -- | F F T re T r s F tr t -- -- r l a o e ,-- a -- s --r -- T e--| E F F n a T e| -- F-- e -- -- |T--i -- T-- 10 p12 M403 Mechanism ofdierent FFTAHS'OopnropjedctannudmIbpeorpr0o3t1i1n2m68e5taboinlAiCOsE3mL-CETP mice study (Jo t --o -- = -- ebe =e --= ---- m] e----| = = = r rfreese-- = F = T V =f F --a ------|---- | Fo ----e--c-- i i r ------Fr--r e ----n =----) -------- --a=] FF a e o = i a HE r s r ---- r E a e e e ---- e E Tr ee ------e ---- e--------+------| FEFoo--r--e --1T 1 + e 1 e ---- -- ----]| F T E e T T + a -- T ss-- ---- -- r 1--%-- m ps M803 Mechanismofferent FATSH' opn padamdaImpoapraot4ein13m6e95tals In ALoE3L-CETP ice Appendix VIE Plasma trae iyceral states I F ll llew esme eeee eoe dcm = F t F e t t f e t t r i] t a e ee ee e fe -- ei e| F C = n f ] + r Ee ee e Fe o e ee o + -- F E ----t-- e t te t er e i w p11 34803 MechanismofGeren PA'TsGopnroIjedctannudmIbpecprr0o3te1i1n3m08e3 taibnAsoo t3Ls-CEmTR mice Appendix VIIL plasma ree fatty acids Stuy2 Lo [e ToPo ee me T a e e e e pm ree]] ea e e 1 --r-- ++ h ] oy F 1 --------e a i a a = e ET----e ------e ------ e i i B e ee e e a E F re e] i] E F e d a o e ee] sa] 1 2 i w p.115 3803 Mechanismof different PE"TANOoSpnr'ojpesicdtanndumlbpeoprr0o3te1i.n12m6e8t5abolism in ApoE3L-CETP mice Appendix [= I[ X Plasma ApoAL ee r = rr r r re--e-- r -- r F = rr e T e er = Tr| T = E e u s r ---- bi i t o e r r e r t HT J-- + r ------ ---- F F a EH ---- T r r e E ee e e e a 5 ET r ong -- r ---- o se F Fe e RT a) e F E e T % e 1 ----] 14 p.116 3403 Mechanismofdiferent PETAHS'OopnroIjepc annudmpboeprr0o3t1e1n2m6e8t5abolism in ASGE3L-CETP mice AppendixX Lo = Pl[ asmaP CETPr masEsemT ee e rw FF e e r s e e--s-- F i r a r r Ft F o i(ereeee--a---- a Tr ae Fita-- s | Ee J T a|e------ha----| F T F I --r r -- -- ---- e -- e-- es-- --a" --a---- p---- -- ee -- || F1 =fTzt+ T ---- e 71 ------ ---- --i---- --= fo a F oi ess -- F tt ------| us p17 3M803 Mechanism ofdifferent PFTASH'sOonproljiedctannudmpboeprroten031m.1e26t8a5bolisminAPOE3L-CETP mice Appendix XI Plasma CETP activity cepa = T a o e r sTem---- = H t = a r T r a F S Te T ] T = F nr r 7 r =e r r v r E e r n r r R r E _e r T r r r r e T e T | e r e a T e e a e --r--ea ese e e 7 -- --------T J = Y + T r --S---- T e To -- e e -- r F I ri e ee gE ----1 E t a r ----1 16 p.118 3803 Mechanism of diferent PEA"ST'HOopnrpojedctannudmobperro0t3e1l1n2m6e8t5abolism in ApoE3L-CETP mice Appendix XII Post heparin LPL and HL activity ef m F F a rer a s a 3 0 " e Ay e e = F ritrir------} 2 F Pr-- +-- e -- esT ------ +--a ---- h------ p0 p -- h o --i---- -- -- e -- ---- 4 --, u h--, --e t , ---- ------ -- V F ---- a F + F ) E F E |-- -- i r-- -- ---- -- E -- t ---- r s -- t---- ---- 5------ -- -- E p PE i t ---- | 8BE F E-- e r----t -------- a -- --4 -- 5 T ----| e E a eee h eeeeeea il-- lae--n--o--n---- :--k ----n hs4 -- ai-- --t -- -- + H B EH-- r -- T r --i -- --) ----#t-- E E r + s -- -- ---- -- = rt wr p19 M403 MecohfdaifenrenitPFsATSH'OmopnrIopjiedc annudmIboeprr0o3t1e1n2m6e6t8abolism in AGGESL-CETPmice Appendix XIII Fecallipids Escalneutralsterols [oo [ [|1 C oyoe smms T[oomw wSomeenTaeen.s omaose]r] own [ow [ae | ET OEY--Toes weTe oeTea 1 50 || SS--YS--T(oCe STC waToX Ta| r To ee oe[oeni Il T | CT SS ox--w T[oS oms n[[oessso I[Y iae2 e[weeso||| oe, F --e ------ wT sr e To eTe| fr F s om ss o e TonTwaeeo T [aaeeeTa |ezwe]] o-- m-- se1sew --TToC oen[oseaw[[J oasm ||aosm||| a 7 os --Toe 2[7 wo|se[ae || FT o wess Toooeneo[Tweweeee|aaanne[T|aa3em0|] PE c ---- ----e eo eneeeon2Tie o 2 sT Tioee| PE To e os[TewoT e |Toes Taine|| e ToTeer Teee ES -- |-- I ae | 1s p.120 3M903 Mechaismofdiferent PPAST'soon tiecdasnmIpobpro3te1ei1n3mr6e8t5abotsm inAPOESLT mice Escalahytostorols EEF E totamlphiye tosltgerremolosswexncre)tion ||_a G__r_e_e_r_%fofophygt] ossterorls _a__w__]_| ST 5% ToeT7940 eae | |i=-- Tss a----aTs1eees | Tw s es T|ae2 sno| lc s sa A r r | C oue [Te eoanr E [e eeeoss n | [TTe ew] | sese 1 asa Ts ees Tes it e Te ese a es ee] n | 5% wei aoe Tes Teor eeesges Te9 e4 s %da0 | eso | | 21 see 1 260s i013 1 e383 oon 5 sesTea esa T e e S oe we w Te s on nT Te ses een74T T1i eaean snrc]|]| T ea se Te ea a T Tea s ] ] a [aeaast| F ---- e --(--a 1 fee |ss ase To ias6 |ees| e E| oEe--T -- s -- 7----(e a -- TTT1 ee eese|es7 ewes | | oe Tan eeTae 1 p.121 34003 Mechanismof rent FASSnepis amdanptealpSaianmsts inApaESLCETPmic Escala acta + FL r mE ebe e e n e EEea eeea ePame) Fe e e oFr-- b re e r eer ip r r ee ra ei reer e ree e e e r FF F F rar o rrr r ere e i e re e epe ee e E e e ne e F pF e F rae --r a r r ar e te e ee rr ierr a re a e ee e e a e pF L om C i ere eT C e e ih ee eere e] e E E E pbep e ee e e re e err e e eeeeeeerrae EE EE Hr r S ss e r e ee r eea eeTe e a ee p12 03 MechanismofdierentPEAST'HOonprIopjectannudmlbpeorpro0t3e1i1nm3e6t8a5bolisminAGGEIL-CETPmice Focalfatty acids EE lIarea om mS m vmot--e--e ---------- m 1S 5 ee1 1 ee 1 ae e 1 e 2ame 1 | F I 1 --e -- e 1mB 1 Jn 1 r 1 ne 53.me 1. || m e r raee m ee e ae] F EEee 4 -- -- J2 3J S C.5 aJeee 1. 1r1e: | fE meae 12eh 2 e ea ee 1 o1e | Ee e | -- a m4 t3 e iba 1a Ee 23 1 1 E EF TEr,re 14 3e 1 e3e: 1 a e e3e E iEe1 1 1r1 ae r r 1 1e1 e1 e2. m o e 2 e 22n y 2 ] 1 fen p12 3003 Mecha ofafferentpTA'H 0p1e5cd snmdaImpaprtan4m.1e36t05ab nAGoESLCETPmice Fatty acabaiance [= I [ n eesE iy|[meonms aon mss aenaio)oni ||as nmiit pseoisseenn| Ee ne---- -- 7 -- --F ---- -- -- 1-- -- -- = -- -- -- By =-- + oh F t -- t t --1 r T -- + = t-- a-- fF oe---- "1 -- + ------ r -- ------ --1---- -- i-- Ft -- a a a a t F F ---- r +---- a-- -- -- F--o -- --i---- it a t m is mt----TSpT------" tsttes wsaoin---------- CE= E ErlEreEEres F EEe rE er s eEHe eEee r e em r ee eee e [eooe eo ] Cs e= e ee a e= Ee H E F EFEEEe r e e ee e e 0 | aesTonTT aeTse us ees ToseTwas | ES E E C e eeoEe E E ee E e hee E te CEE EEoeS EEeJeeSe E e S e C e T e e 1 e e | CE C eC o e eo r e n hs em n e e ree n e s r e=ie] E E Ee rer re e e ae Foes EF e P ohamene r e nE REe e e Eea Sa p.125 M803 Mechanismof different PFAST'NsOonproIjpeicdtaundmblpeorpr0o3te1l.n12m6e8t5abolisminApOE3L-CETP mice DenovoApo synthesisandTGaroductionperAvot Ee F eo ee e e re a 1 Pa T 1 tt | F F T e e e a e ae es e e se e F o EE e e e r r e e S--| -- F r r we Tee a e TeeT ] e F e P ie e Ls h e a e F e are a or h| u f e e e Lo anLee r e e e e a E H r aF e o T e e E e E e ee e e e ma m a e mee ) mn | r t e t ee+i --e--s---- 3 --| 124 p12 03 Wechanism ofdfs PATSr'omn eitamnadrTtpepsr5ten1m0e8t8als inApo S-CETmiPce colodmpositoeirAoccna Lo e E Te e e aerr] a E E Ee e e n ae E Ea e EEE s EE + n a E a Ea + E P P He a e = e e F F F t en a e Te | g Ea ee H F = n e ) EP e a E F ta t t r ] ] us p.127 M803 Mechanismof diferent PFAS"'TsNOopnropjiedctannudmlbpeoprr0o3te1i.n12m6e8t5abolism in ApoE3L-CETP mice Appendix XV Bilary bile acids, cholesterol and phospholipids lI leflow ME l -- T re vcsrr ( Ae a -- TY w--|| ieeee Ts ooee eeer Taee0 wy[CroeT wT[CoeCuT[P waono [TnCowOe Eao | T ET EO 0TF0 T TeCETTaE 0 ET asTTeT m 5Toe ow owB a ere 0as0eese| F e [Tee ee TeseTee e e rr T Taiea o e esoma r wema [ra oauoT|e s waaei EC 0ECEE 0ro | 3 F rrr reed Ja BC aXC ae| E ET TC CCCTB T CTO C ETT 0EYE 1ToenJ e1[J oewe[ooE |nolosno[ue osnTa oonnltorneo|] i I h Searaee e7 e) EE 3 0 1 1 CX [ T TT oToi 1[oieTonT[oer oe[le senTr|sasaeen[a |jsouu] e isTe se Toeosoe [Tosseo[Teaatsieoo[T6aasest[rToesnese w aone | e| wan| uns| P ioTsao[ee esee[oreS o Toons[e aise e [one|a so| ee E r I -- 1 12 126 p12 3903 Mechanism of dierent PEATS'GopnropjedctannudmIbpeorpr0ot3e3i.n1m2e6t8abolism in ApOE3L-CETP mice Bileacdflow [om | oe [Emer Sem a pe --]LE oe rn [enn[Een[Sonn]Son] ou] e F F 7]n ee e es{1e a 247 s e eo oo a] e a] 1] a s aos | veessTess eee 5 a6 1 009 eer | rota C 1 se7i210 2201sCoFs t oe lis risos in]| a Ri ee oe] ee Teo] J3 | [ eEr r a o Tora r ee a e e a e ] e ]| h 0 Ye t 0 ST ] on e 0 e ea7 e e a 7 CE eee eeTe] IEr 2Toso ose TC0sS aee r esr1e 47s e 50s |] sao || Fs oo ean s aeoe sTo e To e a n . [sTr ierwe Toeer sisse|Tie e oivoeTTsm o e T5e0we 01ioe a ne[T7] as]| pmmouovtvieeeds] ECEEaninEwronEg, arly sn flow, ater 30 min adustd0 mous no wim anon TMTeoaiimsseeei11sss mmmooouussssee ndmextdwwdaaurrmmnsssnsromukonshess 2 p.129 M803 Mechanism ofdifferent PFTASH'sOopnrojpeicdtanndumlbpeorpr0o3e1i.n12m68e5tabonlAiposE3mL-CETPmice `hosoholinidflow 1[Eonisons isanTianISrone ism |To] ST CS 710 C 0 00e 0 CC J CC | s A J CC TeTL eTe oTe oeTseo] ncGOe EE---se sCTs[eeYW[eCnY [ae[0BeCn an] Ee F Se f E Tse s 5 E e 6T BKaCe e 6i ae | CE 20 J0 | FT o 7 eoTC oe [es [aoT[C iae ee[1oie1To53 or]| eosTTeesaTooo TLaaieeT[aassa |s0a0[|saeoor| ee TeneooT[Tosene [Tmooenns |Toeees[TTaesmeey|eseaee|[eesooni]]| SS J ET DS OS RO CC or4 iTTeee ToreTees TeiT Te sTTeaen] CN mmmooouuvssseee 72 Mmmooouuvssseee 111383 ee eaeo oere[a a[a er] CoaSn wTroongr, ahaT lnanye flow, oer erTie 30 min adjusted Te Te ue] mmmooouuussseee dnnooettdwwdaaurrrimmngeennaoonuuaggehhsnests mouse not warm enough 120 p.130 M403 Mechanismofdiferent PEAST'NsOonpropjedctanndumlbiepropr0o3t1ei1n2m6e8t5abolism in ApOE3L-CETP mice Ch[ olesterolflow o ea Ce e Tr a] E 7 E [imir [30min 4. wirTs mine 0wieBaR1T%min3 5Y5o5] o = Te os i oeesToe se Tg s eee a asee Te oi i osCo OB 0e 0 T] orc E MMT YW 0RT | [R i o 15o 0[e ei[s ws ee] S E TosTC osTC oTe S E os1s X 5Tisoc[Tss3 eo]] A | i Tob n oTe ol sToew[t36Se 7mIisr alois essei oT s] oo| EE 1 oC oTotC TonTC 0 oeTisX Tia Tio] D 2l EB To:sJ0TCoCsY0tToCKe0TW aeCC s0 sTa2 u Two]| r I IS :BCC CCaSErs s2 Cer C3 e 0 e0 3 TE A 3Oo | I00CF CET CJ C CT 0 A0 EE TToonnTTro5 onTTC oooeTC ereeiTTC eoesTe usersTeaes]] ommoouuessee?2 hCOoaunEscewnTrootEnwgN,aEhnardeElnyouhagnhy flow, ater 30 min adjusted MTTooommeee1l1dss mmmoooiuunsssee nanooettdwwdaaurrmmmpeenanonvuseeehthesa 12 p.131 3M803 Mechanismofdiferent PFAST'HsOonplroijedcatnumbpoeprr0o3t1e.n12m6e8t5abolisminADOE3L-CETP mice AppendixXVI In vivo clearance of VLDL-Iike TG-rich particles and uptake in liver -- . fBier c CE BCTR c T1Y R7 CTY.BO:3 - -1 ||| o5)ut C 2 sel sea1 l snl s31e1o 7 3 eml 5u3l | serumorca (2 = 100%) xSofO}RES or l a 1 l e 2 i aa te ae a| G -- r CATA mt nel srnslr snls sel a1ie] 1 es an7 | -- sdeCal oonl)o inlol--oinl oo ul 1 ool s1o. o 3| orca orsTazB34U(T30I05O15N) ve S [EER Cma CTc OTo e ) r v or ie i e o3a a o1s nl | (0 0 A 1) 1) 1 i7. --e----| 130 p.132 3803 Mechanism ofdiferent PEA"ST'sNopnrojpeicdtannudmpboeprr0o3te1i.n12m6e8t5abolisminAPOE3L-CETP mice EE--CTTTT-- o . wo oJ3 [TE oorsoo]e Tr on tooo 7 a ta oo] esosa o iemag a amlo oolr3| E ETB )T r C C1 Y.S0 t )|| serumoscar aw 2. 100%) Fr1) . 2. 1, | SFoR i eT r 1 -- a 710--r a --e --a -- s -- | CcRE=E mo esolmsral osresl eei1 [ en oa roya 4 [---- eE e ER s R a 1 ea i H ) r S me{ETm ol ou1n]C son son san! sal 1 eal s1a7l 4| orcaorsTRIB3UH (T%0I0O51N8) PrlIeeot fBE--ET so T ol--0a)lT a --ow3]s 2 iol--P cala eale onlo-- 3)| rEoe a rs) 1 | = p.133 M203 MechaofndiiffsremntPFAST'NsOopnropjiedcatnndumlbipeorpr0o3t1e.in12m6e8t5abolism in ApOE3L-CETP mice -- EF3 a C esT l ]a2 lray tex11 El oa senunDecay 3H (2 = 100%) F s saeeeua a sa l s 7 x| ofBTiR owl sasal esol u1.l1 e G1a .B se o. l| CBSE oraloo lee sar--sor---- B E FE E) T T OC as OCs 7 o)| MousaORGAN MASS (3) rcone eE EaErs r i ar t oialTo e Emop riH ena t sa oo i o r d oc OC) C7 E25 BCT RCT| `ORGAN OISTAI3BU(%T00I0O81N5) m s = er R E aEc R) oaE sTvoaE r--e l . aTnlasoleSRE t 7. o I E MO ome w o ) a --wr s o5r )| S sete tab m2 p34 M803 Mechanismofdiferent FAT'NsOopnrojpeicdtannudmpboeprroten031m.1268e5 tainbAPOoESlL-CiETsPmimce WOE wn ce un nu ws 3 5m 1mm| Ea 7 Er 17] TE)R--Ee)hr--15air 5 | semunogcaync 100) i e 1 5r m 1)m e . 1.|n53: 1 1151.. i. ||| EA O mn rsemw smmeontmvcedmonl ra7lm=e,nv--.u7s1i--ou1t 4| p--v mos Arr welI owl--o1750 o1on)!1 som oul om71 --oi4d owl 1 sald| onaanorsTmu34T(0I05O15N) a t 0 me C mera ms11]) me aa 57mr.oma 1 CY ----4|| 1 p.135 M803 Mechanismofdiffrent PFTASN'sOopnrIopjeicdtannudlmpboeprro0t3e1i.n12m685etainbApoOE3lL-CiETPsmimce E--CTT-- r 3 n 1 | 7 me. 1. 1 am. m5e| 0 | serumocca an (2 = 100%) m 1 1 11m m1 r |pm3mm || AOs irmey]motn] tial es7l av:olafowl iss o3nl 4| Mouse ORGAN MASS (5) rel oGcIr SiG cr) e cr cgr)mirng oim | onanorsTRzs30u3T00I05O15N) C 7 5 I 2)C +. | i. || FE 1, 1 | i1 15) 15 i .1. 1 || 134 p.136 E03 MechanismofdiferentPETAHS'OopnroIjpectanndumlbpoeprro0t3e1i1n2m6e6t5abolisminAGGEIL-CETP mice -- JPE R 1)e 1 a| FE 1) 1) 1 5 7 m 1 ie|| & Loonl en] sas] eww] eis] eden] sol | semumorcarsac ca 100m) EE RmRC.S IC) S 10 R e01S o ) n2) R o 10 r1S .)a Ral--a s1 eaa r)--| ESR --Gal aw alow wa--es-- ERE o oon oont ] oul ca ool ool l oa sel ) om 3 Mouse/oanssan Be<E r E LEa Ta taiae e rasaa 1 e1r| [rp---------- R S EFE.E Se C e m taE a rah --oR Rr ea tce orE oura a a5 a aR ar .e e a t 1)a a 13s p37 M403. Mechanismofdifferent PFATSH'sOopnrIopjeicdannudmbeorpr0o3te1i1n2m6e6t5abolism nAGGESLCETPmice E--TTT-- 4 1N. 7L57 5)n . 1 .r . mm||| E5 FaEEo--E auraa-sa aar a senumorcay sac 2 = 300m) fT Toos Too Te r Sidi) BIE Ame 11 711 1 c r+ 7 e ) 3e 5 | E of Eo EE nTea T Sr m os od on e o ew ee rr ] -- (r 0 ev.L mm e H mtT )mE t)r mr t ) 3me s | B 5 3m1 1 5 oneunorsra4ncu(riosotn JPoowttei=Er e rm1 i a r 1r ae 7 E 5. i em y| Eten F1a 7 1 ee. 1 | 13 p.138 3403 Mechanismofierent PFATSH'OonpropjedctannudmIbpeorpr0o3t1e1n2m665etainbADoOE3lL-CiETsPmimce -- Epfo i F C r aTro i C o Toon n a Toop EgSo Lose soanli oa senumoecar sec 2 soo) R r a r a netl a STi B Eo --or--sr a--ear--ai oes--ws--se5----)| r fc i| S FroC berC Cr E C) a T 5st MO te| MousaoRGAN HASS(4) E we en EEyE SIE--SeE r co1E ut--c1E i7p--T ta --e tE ir1--E oi1--E --)| oncaw orsTRIB14U3TI00O57N5) pfonosot o or a a al Eba oaa fr BREESE EE a-- i p.139 M803. Mechanismof diferent FAST'HsGopnroIpjiedcannudmpboeprr0o3e1i1n2m60e5tabionlAiposESmL-CETPmice pe] B7 E 5 13 1 1 1 71 1 17 115151] .1+c 1+ r 1.3 ||| er 7. 5. 3pe 2 3) | senumsaot2c= 0a0mr) er 7 =2.7) 1 1 | 1: 1 7 ||| 3 5 +5 i | eo ---- S e a me me.mE r e T TR1RHt)S ae aSRrP |e H a a eH a.| onanrsTamsucrivoosn) c SER r Sasr ar 1Bre)ac o 1. . 11| b mm1mut1a 5mmamt|| fr E 31 1 p.140 W403 Mechanismofdiferent PFAST'HsOopnrlojpecanndumlbiepropr0o3te1i1n2m6e8t5abolism inApoE3L-CETPmice EE--T-- mtmm m1 rm mr mt Ar S aa s r a 13)me +em v )m sn a mma 1 w s 3. || sncaorsewc 12 00) d| w 1.5 1 we1l). Ewa5mo1 1wRmeCsa1 B lut 1 1se a5 ad||| a OC Cr E --CaEa )tuCT nCTt)t --w1o) tCY--)e whCEr----| [---- E F SR a hahi aa 1ms. mm)mrm1 7 | roan orsTarmuIon ac 3 0515) i 11 s 1mn 5 B i: 1 1 3 1 11 || 1 mm| 19 ss moS --T ------ ----seston ssm------ SB li I1r :5 1E67e 4Ea i e deTosTaTos Tu] S ah . i E. Ym--. --a -- [SrTree en Tree "heeded 200000dpmy200 pi I a ee re IF [I P FE | TrE e he E [Treo esToseTnTes ss1 osr Toi 1"oaee b s e ee e TosoTiaTse Tae Ta00150Hosa T0200 ToseTotes] e cr =| l e S f E aE e s sl l H E e IEe e IEn R es ReER ue oooTses soaTassTaosTosLane1 ogee Taz1 oan | ee . ooTes seaTasToToa oon Toso 1 os] I re TooTress eosTrans vesTan aweTosa TonTote] EFCEE ES SF S f E F F F=oeEoeEE Ee e r n e o e e r ne e en e e E ee e se e e e e SmRs n Ree eErSsS [ieTooTse seeToomeTa amT0200 ToeT0163] p.162 303 Mechanismofdiferent PTAGonpISrdecannudmpboeprr0o3t1e1n3m0e8t3abolism n AsoE3LCETP ice Appendix XVIII Liver microsomal DGAT activity T `proteimni maiciromsomem s.| c"Gs mAs TaTpsctrioytons | ms ami protein r [ 1 T 7 % Te] es 7 | |r oa | re Sr] e Tw l e To o | pe io[in| a fe, | F F ---- --eee-- -- nate-- --e a -- -- i-- -- -- a-- p -- -- a ---- -- -- -- a HT e a t-- a-- i] --T a -- ee e r H ----t ----ona a a 2] 5S ER Tre se] i i ---- -- 1---- -- J F = --t -------- P Te r oToveiels rDONTe1 E eoomedontsmemramen|tEy ose oe] 1a p.143 3203 Mechanismofdiffrent PFTANOoSnpr'opjsiedctannudmlbpeorpr0o3te1i.n12m6e8t5abolism in ApOE3L-CETP mice Appendix XIX Liver lipids r [T [Tlr] eeo lr/er [T [cwh e eaT[[ewsseco TT [ivms oa_| rrr erreae aeee wwesa | [rei r |e =1 T 2 T TTo oT TrT oTas sTTToaeseeo[TTemeoa e[vea5s3r0|] N 8 o T EYs FssWTasee20 woss fe 8 io IsTT oT 0oes "oossTa20s 6 |e30]2] : ESTeTJ oT e Tie2 s20TB a0 os TasYC sWTO76F s || EF r T T J o CW 2 seo e 20 J eiesreTer o ers Ties2 aee| s oTT e o T e reeTe e eeTe eeasTTe eeeeTTo sees T ree reeiTr esesa or E=e E EFT CH JTos ae eXsWTie0 n x io I so e 0OS Ts e T wo|e | I S ie srJTo2 o WSsTaEs Ei F CTTore e0r e T0 es ee e Tse a s me T F JT r0 eeT r0OaoesCT eom y eae T TeThsTes 02 p.144 3M203 Mechanism ofdiferentPEAST'HsOopnropjiedctannudmlbpeorpo0t3e1i.n12m6e8t5abolism in ApoE3L-CETP mice Appendix XX Liver microarray analysis TOQuayof te SEE Open ---- TlirvaenrsocfriApPtoEmSeLanCaElyTsPisomficeeffeocft3Ms compounds in I= p.145 M903 Mechamof frenPA'TsG repicd anadmIbpeorp0r3o1e1i7m6e83talsinASoESLCETP ice Contents #L E e mM me,i1 bh h M mi T s . Ti H i : 10a [3 M803 Mechanismofdiferent PFAST'HsOoprnIojpecatnnudmpboeprr0o3e1i1n2m6e6t5abolism inADOE3L-CETPmice I tanoducrion TR eiyt edT oe ecsprr--TT)iAA--ERA-- SCETrm--eekS-- aoor--ns Fo SIed SHBoFaEeOTmvep0fysholoonneeo. rcTohtmrpcoosFo9Siobfpofod Br Ti a CTormept siesieynoefesnoosChinb2p86cpchhosmpFaep scs fu 195 p.147 3803 Mechanismofdiferent PFAST'NsOopnroljiedctannudmpboeprro0t3e1i.n12m6a8t5abollsm In ApoE3LCETP mice 2 Mebods BRYA bendmerry bien fiiAAcAAowrnntliayonnedstfscwdeimescnrodfpaoAdiPrcSyILeCfemEeYiTe,BAGbrregeuiegcaSoepbfreatr0 1 Gms dns Qubeeoetceonammttooefiiem,nnsoAnR AdpoGiiwEepRufpderArpion0esvaienrB gtsoSaos doFptespeee vsacCoEtuLoft i (Ci,abeC riydoboe ordsn eh e4sdn1i)sseDposean.senConimedsDFeytno1Et5n)t bie8oreraeeenroed 3soorSpwoliioisahpovboes.spemrfoecendwtelg.esebbemdetf i a dbe G s e evtenof0sl(g i pCobc o ST eee b s Gn i olt kt .dicl e ms oilny eshnemdTdoonh echSsnveetdpC.coehretenk ldnr g1vmGs reosas friymnoitflreesoeecbbbpr.daapisernweepIpaphriouss hetn.iegptdpcorotyhae..n ETreomontierspyiawr.peledveliag eesis a convent x Se L eya iti r et h 0pee i ps ed p oFeseKon es emeit anne oCeopp anBriof n pnCSA)he or 6 p.148 3903 Mechanismofdiferent PATSH'OopnropjedctannudmIbpeorpr0o3te1i.n12m6e8t5abolism in APoE3L-CETP mice 5 Resuls 5 Dla pre t eC1 ahedpni ar8teoscdlaFpOiySphmoeFbseFeeL endf(e7)5e2I4ABa HSS.reIreHioeSc b1dy o750nt 05pSppreeesen7w1t9e5 1.1 Fie Nee of amy xned pen = xh of 8 sens JeFp eSe bpeosr stvrianott 0l.4 aypxsean bnseo Flddwch5ofgbe H eFribpoef3rnacoaee4 Prv13iep epposipbyiSecodebyp9tHs14B20e5.f I p.149 303 Mechanismofdiferent PEAST'HsOopnroljiedctannudmpboeprr0o3t1e.i12m6e8t5abolism in ApOE3L-CETP mice er J 0" iFp at2tseoedntgnSonormiaaisgibl ry lpeny dsees ry --regros Dames edn dg ripbr e d 8S EOS 5 pene 50 ouA Peesntonetoeitoaafs ynesaTenel eawh7i g pfet scsofPAaeR4teetoneeended i ey cnet 1 ep oto ot a a ht eei vinTaomms 3apptodpYp h Tvrduest2i d6a?rpeepeo arpoltlpdpeddF1ea35ep.sbTyoetTFFbsHSs.dOa18Fn1 148 p.150 3203 Mechaofndiiffseremnt PFATSN'sOapnrojpeicdtannudmblpeorproein031m,1e26t85a.bolism inAPoE3L-CETPmice J nes sn rTe eeg sleofpe e sssendd 1shi eemecet orol]s pHCuLebErlnmpaeyrobbaBisLeysoonVetBLkWsDe.sSekipse ,sric ei.oPLhtxH4eDLHnDLposetesteon $23 TaDaiiccreosn1Gowces yiobssaoffenopssihdobndebatdmfiympobfpnre, mededd2es2 eenvtareafrong eevlae srtweoptcsid95bGreenOs.1csons SpSeoe mhateeteea,y SiddolWpei:tha.sie!asyboo2mp3bv.s.iN l.gn)ho oscptheds. tcteol 7 PyES Tbhfoip solefnppe,se1ne73ey k posroe rdrIaEvSed1c63 ro1n4shecPvTOsoso3at i orbnndlepietysdvoie1ehrby3pnCoeTgselr.eperAsssclnee ouofnrGcsnsiprugticsnbilstyogiiefmeeoeoesnfal2y TPiSensfonoPecueSoboerdFrole.tcAcomaRe.TotApbdnp ie, oberh hr5p0nrccen + 5 Pe feFphrguei ispehn mnmfibg cosngiyovn ibaddgooee osgysosoor)" TovaLmpyenC tTuoohot otwseebybcpFrrHeoaSoifnpee 4opp PedOosfTrhexp ce edotdfoohe txgpcr+ooesn nehnaeor dpHfoplvseetof Fe1T0hnmeecamasmm4m .ectroypcoa oisTlPhesH1rd(rhF7tod 0s5tcio)rFvottrosspweees nnpdoptliln 1 ss inaarnkF PO.tAeTE SnaCPFO0f8b.tTeeocsoce vnsiBti nes oe5t3os0tsoyonepe.sobLpeyle i Ep 109 p.151 3603 Mechanismof diferent FTASH' nreljescdtandumIbpeorpr0t3s1i1n7m0e6t3abolism in AvoESL-CETP mice il re HE BIG 1P] EiEES < i === LIE PE [ +H]l EE= -- RR e -- Ir de a FTaresm.pceeiof ts end ko ke Sp oe 150 p.152 M203. Mechanismofdferent FATSH anp1r5edcannudmpboeprroten031m1368e5 tainbAsooE3lLCiETPsmimcs 3= ope Roeser of or pots ox 3 i eg be ist p.153 3M203 MechanismofdifferntPEAST'HsOopnroljiedctannudmlbieporpr0o3t1ei.n12m6e8t5abolism in APOE3L-CETP mice 4 Conclusions e 18bseerbs Ailnrdoisfy nssppyoe 1fnortARODpLCtETt? ToGyrS1ewde0st4,n1obprwcsieoesLodyagpsdSppssnebddb.CosA mivaenrs FpBu tnr oevoarnypesegsoen,tSpeeedpesodstenTTSBPeHtpwed 7t0STpFSwnot Sriemtpoftgemn es sh no eo sn 0 12 p15 HE ALTAiS emes EP ATT re poem EC sSEeEr lr] fr rian e A f --oe ----E -- i e mE n-- ] e E ] JE ; oa e =:Ese.=Hsl=].]= . poe EerE leE ] pp er ne sm EpEeaE ] FE n e e e E e erE ] er i BEE] e[e7 pm E e e remmee m mK e e ei | e] ] e]] E Sr G pot cesrance = fe pr a D frosme Crmeerreoo ee e eet s rmr ] e 5e1 ] ]n 1 TM a - D Deer -- e]