1、脂肪肝最新研究摘要EASL解析PS066FXR AGONISM BY GS-9674 DECREASES STEATOSIS AND FIBROSIS INA MURINE MODEL OF NASHJ.T. Liles1, S. Karnik1, E. Hambruch2, C. Kremoser2, M. Birkel2, W.J. Watkins1, D. Tumas1, D. Breckenridge1, D. French1. 1Gilead Sciences,Foster City, United States; 2Phenex Pharmaceuticals AG, Heidel
2、berg,GermanyE-mail: John.LilesGBackground and Aims: GS-9674 is a selective nonsteroidal FarnesoidX Receptor (FXR) agonist being developed by Gilead Sciences for thetreatment of NASH. FXR is a nuclear hormone receptor that is highlyexpressed in the gastrointestinal tract and liver, and is a primaryre
3、gulator of bile acid (BA) homeostasis. GS-9674 acts in the intestineto produce FGF19 (FGF15 in rodents), an endocrine hormone thatdown-regulates BA synthesis, lipogenesis and gluconeogenesis in theliver and increases energy expenditure in adipose tissue. Both lowFGF19 and high BA levels have been as
4、sociated with the pathogenesisand progression of NASH including the degree of hepatic fibrosis. Inthis study we evaluated the therapeutic efficacy of GS-9674 in micewith established NASH.Methods:NASHwas induced in male C57BL/6 mice byadministrationof a fast food diet (FFD) high in fat, cholesterol,
5、and sugar for 240 days.Animals were subsequently treated with either vehicle or GS-9674(30 mg/kg, BID, PO) for 90 days (n = 15/group). Endpoints includedsteatosis evaluated by morphometry, liver hydroxyproline levels,clinical pathology, NAFLD activity scores (NAS) by histology, and anoral glucose to
6、lerance test. C57BL/6 mice on a normal diet (n = 15/group) were a control group.Results: Serum cholesterol, AST and ALT, and liver steatosis andfibrosis were significantly elevated in vehicle-treated mice following240 and 330 days of FFD relative to control mice. Compared tovehicle-treated mice, mic
7、e treated with GS-9674 from day 240 to 330demonstrated significant decreases in serum AST (192 21 vs. 293 12 IU/L, p 0.0002), ALT (178 35 vs. 267 24 IU/L, p 0.04) andcholesterol (144 12 vs. 321 23 mg/dl, p 0.0001). GS-9674treatment also significantly reduced hepatic steatosis as measuredby morphomet
8、ric analysis (7.4 1.3 vs. 14.5 0.7% area, p 0.01). GS-9674-treatment reduced liver fibrosis as measured by hydroxyprolinecontent (127 12 vs. 320 37 mmol/g, p 0.0001) compared tovehicle-treated animals. GS-9674 did not affect food intake, bodyweight, or glucose metabolism.Conclusions: In a murine mod
9、el of NASH, treatment with the FXRagonist GS-9674 significantly reduced serum ALTand ASTand hepaticsteatosis and fibrosis. The data support clinical evaluation of GS-9674for the treatment of NASH.PS067IDENTIFICATION OF LIPIDOMIC SIGNATURES THAT DEFINE THREESPECIFIC SUBTYPES OF NAFLD AND DIFFERENTIAT
10、E NASH FROMSIMPLE STEATOSISC. 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; 2CICbioGUNE, Ciberehd, Derio, Spain; 3Division of Gastroenterology, Cedars-Sinai Medical Center, Los An
11、geles, United StatesE-mail: jmmatocicbiogune.esBackground and Aims: Nonalcoholic steatohepatitis (NASH) is ahistological definition that groups together defects in diversebiochemical processes causing hepatic fat accumulation,inflammation, necrosis and fibrosis. The identification of the typesof mec
12、hanisms leading to NASH and the discovery of noninvasivebiomarkers of NASH subtypes are central for the development ofeffective treatments and precise diagnosis. This study aims to capturethe metabolic architecture of the main NASH subtypes to help defineeffective treatments and discover specific se
13、rum metabolomicpatterns reflective of each NASH subtype.Methods: We have compared the serum metabolome (over 400different molecular species) of a mouse model (Mat1a-/-) thatspontaneously develops NASH with that of WT mice and selectedthe top fifty metabolites that more significantly differentiatedbe
14、tween both genotypes (p 1E-05).Results: Silhouette cluster analysis revealed that this metabolicsignature sub-classified a cohort of 377 patients with biopsy provenNAFLD (246 diagnosed of steatosis and 131 diagnosed of NASH) intothree clusters: a first cluster (n = 116) showing a serum metabolicprof
15、ile similar to that observed in the Mat1a-/- mice (M-subtype),a second cluster (n = 115) showing the opposite metabolomicprofile (non-M-subtype) and a third cluster (n = 146) presenting anintermediate metabolic profile (I-subtype). Next, we wonderedwhether NAFLD patients in the M-type NAFLD subgroup
16、 could befurther separated into simple steatosis and NASH based exclusively intheir metabolic profile. Volcano plot analysis representation oflog10(p-value) and log2(fold-change) identified a group of highlysignificant lipids (p 1E-05, mostly lysophospholipids andpolyunsaturated fatty acids) that ef
17、fectively differentiated betweenthese two conditions. Similarly,we successfully identified a metabolicsignature (mostly triglycerides and phosphatidylcholines) thataccurately differentiated between steatosis and NASH in the non-MtypeNAFLDsubgroup.Whenthis unsupervised approachwas appliedto the third
18、 cluster (I-subtype), the metabolic signature able todifferentiate between steatosis and NASH was mainly based inpolyunsaturated fatty acids.Conclusions: Our data document the power of serum metabolomicsto identify signatures that define NAFLD subtypes and differentiateNASH from simple steatosis in
19、humans. Moreover, these metabolicsignatures may be used to analyze the individual response totreatment in clinical trials.PS068THE NEW GENERATION PAN-PPAR AGONIST IVA337 PROTECTS THELIVER FROM METABOLIC DISORDERS AND FIBROSISG. Wettstein1, C. Estivalet1, J. Tessier1, P.T. Boustugue1, I. Jantzen1,E.
20、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, FranceE-mail: guillaume.wettsteinBackground and Aims: Non-alcoholic fatty liver disease (NAFLD) isa complex liver path
21、ology starting from simple hepatocellularsteatosis to non-alcoholic steatohepatitis (NASH), fibrosis andultimately cirrhosis. NASH is proposed as the hepatic manifestationof the metabolic syndrome. Currently there is no treatment forNASH although several Peroxisome Proliferator-Activated Receptors(P
22、PARs) agonists have demonstrated positive signals during clinicaltrials in NASH. PPARs play roles in lipid and glucose metabolism,inflammation, cellular growth, differentiation and fibrogenesis. Thissuggests that, IVA337, a well-balanced pan-PPAR agonist (EC50:PPAR 0.9 M, PPAR 0.5 M, PPAR 0.2 M), th
23、at underwent Phase 2clinical investigations in Type 2 diabetic patients, might represent anattractive therapeutic approach in NASH. We evaluated the effect ofIVA337 in vitro on proliferation and activation of Hepatic Stellate Cells(HSC) and in vivo on key parameters of the metabolic syndrome aswell
24、as on hepatic fibrosis.Methods: In vitro we studied the effects of IVA337 on PDGF-inducedproliferation and stiffness-induced activation of Hepatic Stellate Cells.In vivo, we investigated IVA337 in models of High Fat/High Sucrose(HF/HS) diet and CCL4 induced liver fibrosis (prophylactic andtherapeuti
25、c).Results: Treatment with IVA337 but not with selective PPAR agonistsled to a complete dose-dependent inhibition of PDGF-inducedproliferation in HSC. IVA337 also inhibited HSC activation bypreventing upregulation of -SMA expression. In the HF/HS dietmodel, IVA337 given upon therapeutic dosing regim
26、en for 4 weeks,resulted in a dose-dependent decrease of body weight, serumtriglycerides, adiposity index, insulin resistance and an increase ofserum adiponectin. IVA337 also inhibited CCL4-induced fibrosis(prophylactic and therapeutic), expression of TGF- familymembers and extracellular matrix compo
27、nents.Conclusions: These findings demonstrate that simultaneousactivation of the 3 PPAR isoforms by IVA337 exerts a beneficialeffect on HSC proliferation and differentiation in vitro, and on liverfibrosis in vivo. Interestingly, selective PPARs agonists did not inhibitHSC proliferation, pointing out
28、 the benefit of using a pan-PPARagonist for the treatment of liver fibrosis. In addition, IVA337demonstrated positive effects on metabolic markers consideredroot causes for NASH. Together this data support the clinicalinvestigation of IVA337 for the treatment of NASH patients.PS069THE EFFECT OF MTOR
29、C1 INHIBITION ON NAFLD AND SUBSEQUENTHCC DEVELOPMENTA. Umemura1,2, Y. Itoh1, M. Karin2. 1Department of MolecularGastroenterology and Hepatology, Graduate School of Medical Science,Kyoto Prefectural University of Medicine, Kyoto, Japan; 2Laboratory ofGene Regulation and Signal Transduction, Departmen
30、ts of Pharmacologyand Pathology, UCSD, San Diego, United StatesE-mail: aumemura2002yahoo.co.jpBackground and Aims: Since mTORC1 is activated in up to 50% ofHCCs, there has been much interest in the use of mTORC1 inhibitorsfor HCC treatment. mTORC1 is also activated in response to obesitywhich greatl
31、y enhances HCC risk. So, we hypothesized that mTORC1inhibition attenuates obesity-induced fatty liver and its subsequentHCC development.Methods: We conducted short-term mTORC1 inhibition by amTORC1 inhibitor rapamycin (A). To determine the direct effect oflong-term mTORC1 suppression in hepatocytes,we used hepatocytespecificRaptor-deficient (Rpt KO) mice (B). We also used Tsc1knockout (TSC1 KO) mice, in which mTORC1 is constitutivelyactivated (C).Results: (A) Rapamycin treatment improved fatty liver in HFD (highfatdiet)-fed mice, surprisingly however, such mTORC1 inhibitionalso resulte
