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648A AASLD ABSTRACTS HEPATOLOGY, October, 2015 (a) low-density lipoprotein receptor deficient (Ldlr −/− ) mice fed a high fat diet and treated with either antagomir-21, antagomir control (without specific target) or phosphate buffer saline; (b) microRNA-21 deficient and wild-type mice fed a methionine-choline-deficient diet (MCD). Wild-type mice fed a chow diet served as control. We quantified microRNA-21 levels and assessed cell localization in the liver using real-time quantitative PCR and in situ hybridization. To determine whether the effect of inhibiting or deleting microRNA-21 involved PPARα, a known microRNA-21 target implicated in NASH, we also fed PPARα deficient mice a MCD diet and treated them with either antagomir-21 or antagomir control. Finally, microRNA-21 levels were also quantified in the liver of patients with NASH or bland steatosis and in normal liver; its cellular localization was also determined. Results: Inhibiting or deleting liver microRNA-21 expression in both murine models of NASH reduced liver cell injury, inflammation, and fibrogenesis without affecting liver lipid accumulation or betaoxidation. PPARα was decreased in the liver of mice with NASH and restored following microRNA-21 inhibition or deletion. In PPARα deficient mice fed a MCD diet, antagomir-21 had no effect on liver cell injury, inflammation, and fibrogenesis. Liver microRNA-21 was overexpressed, primarily in inflammatory and biliary cells, in both mouse models as well as in patients with NASH, but not in patients with bland steatosis. Conclusion: This study demonstrates that microRNA-21 is increased in NASH in liver inflammatory cells in mice and in patients. MicroRNA-21 inhibition or deletion strongly decreases liver injury, inflammation and fibrosis, through PPARα normalization. These findings underscore the potential interest of antagomir-21 as a therapeutic strategy for NASH. Disclosures: Jérémy Scetbun - Employment: Merck & Co. Patrick Marcellin - Consulting: Roche, Gilead, BMS, Vertex, Novartis, Janssen, MSD, Abbvie, Alios BioPharma, Idenix, Akron; Grant/Research Support: Roche, Gilead, BMS, Novartis, Janssen, MSD, Alios BioPharma; Speaking and Teaching: Roche, Gilead, BMS, Vertex, Novartis, Janssen, MSD, Boehringer, Pfizer, Abbvie Francois Durand - Advisory Committees or Review Panels: Astellas, Novartis, BMS; Speaking and Teaching: Gilead Bart Staels - Advisory Committees or Review Panels: MSD; Consulting: Genfit Pierre-Emmanuel Rautou - Speaking and Teaching: Gilead The following authors have nothing to disclose: Xavier Loyer, Valerie Paradis, Carole Hénique, Anne-Clémence Vion, Nathalie Colnot, Coralie L. Guerin, Cécile Devue, Sissi On, Mélissa Romain, Jean-Louis Paul, Marc E. Rothenberg, Pierre Bedossa, Carina Prip-Buus, Eric Baugé, Chantal Boulanger, Alain Tedgui 888 Two different aspects of PD-1 expression on intrahepatic CD4+ and CD8+ T cells in a High Fat High Cholesterol Diet-induced murine NASH Kanji Yamaguchi 1 , Akira Okajima 1 , Yuya Seko 1 , Hiroshi Ishiba 1 , Hiroyoshi Taketani 1 , Atsushi Umemura 1 , Taichiro Nishikawa 1 , Yoshio Sumida 1 , Hironori Mitsuyoshi 1 , Kohichiroh Yasui 1 , Takeshi Okanoue 2 , Yoshito Itoh 1 ; 1 Gastroenterology, Kyoto Prefectural University of Medicine, Kyoto, Japan; 2 Hepatology Center, Saiseikai Suita Hospital, Osaka, Japan Background: Programmed death (PD)-1 signaling plays an important role of the negative regulation of immune responses in chronic inflamed liver. Its ligand, PD-L1, is expressed on hepatocytes in non-alcoholic steatohepatitis (NASH) livers, and that hepatocytes induce apoptosis in T-cells via their interaction. The aim of this study is to clarify the pathophysiological role of PD-1 expressing CD4+ and CD8+ T cells in murine NASH livers. Methods: Eight-week-old male C57/BL6 mice were fed either chow or high fat high cholesterol (HFHC) diets for 24 weeks. Hepatic lymphocytes were isolated by density gradient centrifuge with 35% isotonic Percoll solution after the perfusion with 10 ml PBS via portal vein and expression of PD-1 was analyzed by FACS at the time points of 8, 16, and 24 weeks. Moreover, after sorting the fractions of CD4+/PD-1-, CD4+/PD-1+, CD8+/PD-1-, CD8+/PD-1+ T cells, mRNA levels of TNFα, IL-4, IFNγ, IL-6, foxp3, IL-10 in each group of CD4+ T cells and TNFα, IFNγ, granzyme B, perforin, IL-6 in each group of CD8+ T cells were assessed by real-time PCR. For further study of PD-1 expressing T cells, we analyzed the blocking effect of PD-1 signaling on liver injury by continuously using PD-1 and PDL-1 neutralizing antibody in HFHC-fed mice for 24 weeks. Results: The number of PD-1 expressing CD4+ or CD8+ T cells was higher in HFHC diet-fed mouse livers and increased in a time and the degree of hepatic injury dependent manner. Furthermore, HFHC diets significantly induced hepatic PD-L1 mRNA at 24 weeks as previously reported. Realtime PCR analysis revealed that whereas PD-1 expressions on CD4+ T cells suppressed TNFα and IL-6 expression but rather increased IL-10 expression, those on CD8+ T cells significantly increased granzyme B and perforin despite of decreasing IL-6 expression. Finally, blockade of PD-1 signaling for 24 weeks greatly ameliorated plasma levels of AST and ALT. Conclusion: PD-1 expressing T cells were increased in murine NASH livers with the elevation of hepatic PD-L1 expression. This regulatory molecule may act as a suppressor in CD4+ T cells but an activator in CD8+ T cells in this murine NASH model and blockade of these PD-1 signaling led to the amelioration of liver injury. Disclosures: Yoshito Itoh - Grant/Research Support: MSD KK, Bristol-Meyers Squibb, Dainippon Sumitomo Pharm. Co., Ltd., Otsuka Pharmaceutical Co., Chugai Pharm Co., Ltd, Mitsubish iTanabe Pharm. Co.,Ltd., Daiichi Sankyo Pharm. Co.,Ltd., Takeda Pharm. Co.,Ltd., AstraZeneca K.K.:, Eisai Co.,Pharm.Ltd, FUJIFILM Medical Co.,Ltd., Gelaed Sciences Co., GlaxoSmithKline The following authors have nothing to disclose: Kanji Yamaguchi, Akira Okajima, Yuya Seko, Hiroshi Ishiba, Hiroyoshi Taketani, Atsushi Umemura, Taichiro Nishikawa, Yoshio Sumida, Hironori Mitsuyoshi, Kohichiroh Yasui, Takeshi Okanoue 889 DNA Methylation Profiles of Fibrosis-Associated Gene in Blood Reflects Liver Fibrosis Severity in Human Nonalcoholic Fatty Liver Disease Cynthia A. Moylan 1,2 , Susan K. Murphy 3 , Carole Grenier 3 , Manal F. Abdelmalek 1 , Anna Mae Diehl 1 ; 1 Duke University Medical Center, Durham, NC; 2 Medicine, Durham Veterans Affairs Medical Center, Durham, NC; 3 Obstetrics & Gynecology, Duke University, Durham, NC Background: Nonalcoholic fatty liver disease (NAFLD) can lead to cirrhosis, but disease progression is highly variable. Fibrosis severity is the only independent predictor of cirrhosis risk in NAFLD. DNA methylation and other epigenetic mechanisms play a role in instructing fibrosis progression. We reported that DNA methylation at specific loci of certain liver genes correlated with their expression in liver and with fibrosis severity in human NAFLD. Aim: We sought to determine if DNA methylation profiles of fibrosis-associated genes can be measured in blood and whether they reflect fibrosis severity (i.e., cirrhosis risk) in NAFLD patients. Methods: Patients with near-normal histology and biopsy-proven NAFLD were selected from the Duke NAFLD Biobank. The cohort was stratified into 3 groups as shown in the Table: Advanced NAFLD, Mild NAFLD, and Controls. DNA was isolated from liver and blood, bisulfite modified using the Zymo EZ DNA Methylation Kit, and then analyzed by pyrosequencing (PS). Site-specific methylation levels (%met) for two genes of interest (FGFR2, cg1385327; CASP1, cg13802966) were correlated by tissue type and compared by NAFLD severity using Pearson correlation and non-para-
HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 649A metric t-tests and ANOVA. Results: Age, gender and BMI were similar across the 3 groups. More advanced NAFLD patients had diabetes mellitus and there were more black patients in the control group. A NAFLD Activity Score greater than or equal to 5 was more common in the advanced NAFLD group. CASP1 and FGFR2 % met could be measured in both liver and blood. CASP1 %met was similar between tissue types and differed significantly by group in both liver and blood (controls: 2.8, mild NAFLD: 3.1, advanced NAFLD: 3.6; p=0.04). Although FGFR2 %met somewhat correlated in paired normal liver and blood samples (r=0.55, p=0.01), only FGFR2 %met in liver differed significantly by group (controls: 9.1, mild NAFLD: 8.6, advanced NAFLD: 4.8; p
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1312A AUTHOR INDEX HEPATOLOGY, Octo
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