脂肪肝最新研究摘要EASL解析文档格式.docx

脂肪肝最新研究摘要EASL解析文档格式.docx

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liverandincreasesenergyexpenditureinadiposetissue.Bothlow

FGF19andhighBAlevelshavebeenassociatedwiththepathogenesis

andprogressionofNASHincludingthedegreeofhepaticfibrosis.In

thisstudyweevaluatedthetherapeuticefficacyofGS-9674inmice

withestablishedNASH.

Methods:

NASHwasinducedinmaleC57BL/6micebyadministration

ofafastfooddiet（FFD）highinfat,cholesterol,andsugarfor240days.

AnimalsweresubsequentlytreatedwitheithervehicleorGS-9674

（30mg/kg,BID,PO）for90days（n=15/group）.Endpointsincluded

steatosisevaluatedbymorphometry,liverhydroxyprolinelevels,

clinicalpathology,NAFLDactivityscores（NAS）byhistology,andan

oralglucosetolerancetest.C57BL/6miceonanormaldiet（n=15/

group）wereacontrolgroup.

Results:

Serumcholesterol,ASTandALT,andliversteatosisand

fibrosisweresignificantlyelevatedinvehicle-treatedmicefollowing

240and330daysofFFDrelativetocontrolmice.Comparedto

vehicle-treatedmice,micetreatedwithGS-9674fromday240to330

demonstratedsignificantdecreasesinserumAST（192±

21vs.293±

12IU/L,p<

0.0002）,ALT（178±

35vs.267±

24IU/L,p<

0.04）and

cholesterol（144±

12vs.321±

23mg/dl,p<

0.0001）.GS-9674

treatmentalsosignificantlyreducedhepaticsteatosisasmeasured

bymorphometricanalysis（7.4±

1.3vs.14.5±

0.7%area,p<

0.01）.GS-

9674-treatmentreducedliverfibrosisasmeasuredbyhydroxyproline

content（127±

12vs.320±

37mmol/g,p<

0.0001）comparedto

vehicle-treatedanimals.GS-9674didnotaffectfoodintake,body

weight,orglucosemetabolism.

Conclusions:

InamurinemodelofNASH,treatmentwiththeFXR

agonistGS-9674significantlyreducedserumALTandASTandhepatic

steatosisandfibrosis.ThedatasupportclinicalevaluationofGS-9674

forthetreatmentofNASH.

PS067

IDENTIFICATIONOFLIPIDOMICSIGNATURESTHATDEFINETHREE

SPECIFICSUBTYPESOFNAFLDANDDIFFERENTIATENASHFROM

SIMPLESTEATOSIS

C.Alonso1,D.Fernandez-Ramos2,M.Iruarrizaga-Lejarreta1,

M.Varela2,I.Martinez-Arranz1,M.Noureddin3,M.

L.Martinez-Chantar2,S.C.Lu3,P.Ortiz1,J.M.Mato2.1OWL;

2CIC

bioGUNE,Ciberehd,Derio,Spain;

3DivisionofGastroenterology,Cedars-

SinaiMedicalCenter,LosAngeles,UnitedStates

jmmato@cicbiogune.es

Nonalcoholicsteatohepatitis（NASH）isa

histologicaldefinitionthatgroupstogetherdefectsindiverse

biochemicalprocessescausinghepaticfataccumulation,

inflammation,necrosisandfibrosis.Theidentificationofthetypes

ofmechanismsleadingtoNASHandthediscoveryofnoninvasive

biomarkersofNASHsubtypesarecentralforthedevelopmentof

effectivetreatmentsandprecisediagnosis.Thisstudyaimstocapture

themetabolicarchitectureofthemainNASHsubtypestohelpdefine

effectivetreatmentsanddiscoverspecificserummetabolomic

patternsreflectiveofeachNASHsubtype.

Wehavecomparedtheserummetabolome（over400

differentmolecularspecies）ofamousemodel（Mat1a-/-）that

spontaneouslydevelopsNASHwiththatofWTmiceandselected

thetopfiftymetabolitesthatmoresignificantlydifferentiated

betweenbothgenotypes（p<

1E-05）.

Silhouetteclusteranalysisrevealedthatthismetabolic

signaturesub-classifiedacohortof377patientswithbiopsyproven

NAFLD（246diagnosedofsteatosisand131diagnosedofNASH）into

threeclusters:

afirstcluster（n=116）showingaserummetabolic

profilesimilartothatobservedintheMat1a-/-mice（M-subtype）,

asecondcluster（n=115）showingtheoppositemetabolomic

profile（non-M-subtype）andathirdcluster（n=146）presentingan

intermediatemetabolicprofile（I-subtype）.Next,wewondered

whetherNAFLDpatientsintheM-typeNAFLDsubgroupcouldbe

furtherseparatedintosimplesteatosisandNASHbasedexclusivelyin

theirmetabolicprofile.Volcanoplotanalysis[representationof

log10（p-value）andlog2（fold-change）]identifiedagroupofhighly

significantlipids（p<

1E-05,mostlylysophospholipidsand

polyunsaturatedfattyacids）thateffectivelydifferentiatedbetween

thesetwoconditions.Similarly,wesuccessfullyidentifiedametabolic

signature（mostlytriglyceridesandphosphatidylcholines）that

accuratelydifferentiatedbetweensteatosisandNASHinthenon-MtypeNAFLD

subgroup.Whenthisunsupervisedapproachwasapplied

tothethirdcluster（I-subtype）,themetabolicsignatureableto

differentiatebetweensteatosisandNASHwasmainlybasedin

polyunsaturatedfattyacids.

Ourdatadocumentthepowerofserummetabolomics

toidentifysignaturesthatdefineNAFLDsubtypesanddifferentiate

NASHfromsimplesteatosisinhumans.Moreover,thesemetabolic

signaturesmaybeusedtoanalyzetheindividualresponseto

treatmentinclinicaltrials.

PS068

THENEWGENERATIONPAN-PPARAGONISTIVA337PROTECTSTHE

LIVERFROMMETABOLICDISORDERSANDFIBROSIS

G.Wettstein1,C.Estivalet1,J.Tessier1,P.T.Boustugue1,I.Jantzen1,

E.Defrene1,F.Kupkowski1,P.Faye1,V.Adarbes1,J.-M.Germain1,

E.Vasseur1,C.Robert1,C.Fromond1,P.Broqua1,J.-L.Junien1,

J.-M.Luccarini1,I.Konstantinova1.1INVENTIVA,daix,France

guillaume.wettstein@

Non-alcoholicfattyliverdisease（NAFLD）is

acomplexliverpathologystartingfromsimplehepatocellular

steatosistonon-alcoholicsteatohepatitis（NASH）,fibrosisand

ultimatelycirrhosis.NASHisproposedasthehepaticmanifestation

ofthemetabolicsyndrome.Currentlythereisnotreatmentfor

NASHalthoughseveralPeroxisomeProliferator-ActivatedReceptors

（PPARs）agonistshavedemonstratedpositivesignalsduringclinical

trialsinNASH.PPARsplayrolesinlipidandglucosemetabolism,

inflammation,cellulargrowth,differentiationandfibrogenesis.This

suggeststhat,IVA337,awell-balancedpan-PPARagonist（EC50:

PPARα0.9μM,PPARδ0.5μM,PPARγ0.2μM）,thatunderwentPhase2

clinicalinvestigationsinType2diabeticpatients,mightrepresentan

attractivetherapeuticapproachinNASH.Weevaluatedtheeffectof

IVA337invitroonproliferationandactivationofHepaticStellateCells

（HSC）andinvivoonkeyparametersofthemetabolicsyndromeas

wellasonhepaticfibrosis.

InvitrowestudiedtheeffectsofIVA337onPDGF-induced

proliferationandstiffness-inducedactivationofHepaticStellateCells.

Invivo,weinvestigatedIVA337inmodelsofHighFat/HighSucrose

（HF/HS）dietandCCL4inducedliverfibrosis（prophylacticand

therapeutic）.

TreatmentwithIVA337butnotwithselectivePPARagonists

ledtoacompletedose-dependentinhibitionofPDGF-induced

proliferationinHSC.IVA337alsoinhibitedHSCactivationby

preventingupregulationofα-SMAexpression.IntheHF/HSdiet

model,IVA337givenupontherapeuticdosingregimenfor4weeks,

resultedinadose-dependentdecreaseofbodyweight,serumtriglycerides,adiposityindex,insulinresistanceandanincreaseof

serumadiponectin.IVA337alsoinhibitedCCL4-inducedfibrosis

（prophylacticandtherapeutic）,expressionofTGF-βfamily

membersandextracellularmatrixcomponents.

Thesefindingsdemonstratethatsimultaneous

activationofthe3PPARisoformsbyIVA337exertsabeneficial

effectonHSCproliferationanddifferentiationinvitro,andonliver

fibrosisinvivo.Interestingly,selectivePPARsagonistsdidnotinhibit

HSCproliferation,pointingoutthebenefitofusingapan-PPAR

agonistforthetreatmentofliverfibrosis.Inaddition,IVA337

demonstratedpositiveeffectsonmetabolicmarkersconsidered

rootcausesforNASH.Togetherthisdatasupporttheclinical

investigationofIVA337forthetreatmentofNASHpatients.

PS069

THEEFFECTOFMTORC1INHIBITIONONNAFLDANDSUBSEQUENT

HCCDEVELOPMENT

A.Umemura1,2,Y.Itoh1,M.Karin2.1DepartmentofMolecular

GastroenterologyandHepatology,GraduateSchoolofMedicalScience,

KyotoPrefecturalUniversityofMedicine,Kyoto,Japan;

2Laboratoryof

GeneRegulationandSignalTransduction,DepartmentsofPharmacology

andPathology,UCSD,SanDiego,UnitedStates

aumemura2002@yahoo.co.jp

SincemTORC1isactivatedinupto50%of

HCCs,therehasbeenmuchinterestintheuseofmTORC1inhibitors

forHCCtreatment.mTORC1isalsoactivatedinresponsetoobesity

whichgreatlyenhancesHCCrisk.So,wehypothesizedthatmTORC1

inhibitionattenuatesobesity-inducedfattyliveranditssubsequent

HCCdevelopment.

Weconductedshort-termmTORC1inhibitionbya

mTORC1inhibitorrapamycin（A）.Todeterminethedirecteffectof

long-termmTORC1suppressioninhepatocytes,weusedhepatocytespecific

Raptor-deficient（RptKO）mice（B）.WealsousedTsc1

knockout（TSC1KO）mice,inwhichmTORC1isconstitutively

activated（C）.

（A）RapamycintreatmentimprovedfattyliverinHFD（highfat

diet）-fedmice,surprisinglyhowever,suchmTORC1inhibition

alsoresulte