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876A AASLD ABSTRACTS HEPATOLOGY, October, 2015 exosome binding to HSC by RGD (p < 0.05) but not by RGE. Binding of PKH26-stained HSC-derived exosomes to PKH67- stained HSC, assessed over 12 hrs, was also dose-dependently inhibited by EDTA (0-500 μM; p < 0.05). Since these data suggested exosome-HSC interactions involve integrins and since all five αV integrins (β1, β3, β5, β6, β8) and two β1 integrins (α5, α8) are RGD-dependent, recipient HSC were transfected for 24 hrs with siRNA to αV or β1 and then incubated with PKH26-stained exosomes for 24 hrs. Each treatment alone was effective in blocking >95% exosome binding. Finally, binding of HSC-derived exosomes to recipient HSC was reduced by heparin but not chondroitin sulfate (100μg/ml) while exosomal miR-214-mediated suppression of CTGF 3’-UTR activity, accomplished by 24-hr co-culture of miR-214-transfected donor HSC with CTGF 3’-UTR luciferase reporter-transfected recipient HSC was reversed in the presence of heparin but not chondroitin sulfate (100μg/ml) (p < 0.05). Thus exosome-HSC interactions or downstream gene activity are heparin- or integrin-dependent, the latter of which requires expression of αV and/or β1 subunits by recipient HSC. Disclosures: David Brigstock - Stock Shareholder: FibroGen The following authors have nothing to disclose: Li Chen, Ruju Chen, Sherri Kemper 1357 Potential of connective tissue growth factor as a novel therapeutic target against hepatic fibrosis Yuki Makino, Hayato Hikita, Yugo Kai, Yasutoshi Nozaki, Tasuku Nakabori, Yoshinobu Saito, Satoshi Tanaka, Ryotaro Sakamori, Naoki Hiramatsu, Tomohide Tatsumi, Tetsuo Takehara; Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan Background and aim: Connective tissue growth factor (CTGF) is a multifunctional matricellular protein reported to be up-regulated in the liver of patients with chronic liver diseases. However, the association of CTGF and liver fibrosis has not been fully studied. We analyzed the significance of CTGF and its potential as a therapeutic target in hepatic fibrosis. Methods/ Results: Using clinical resected livers of 93 patients under the approve of Research Ethics Committee, we revealed that CTGF expression levels in non-tumorous liver tissue increased along with the progression of fibrotic degrees of the liver and positively correlated with those of other fibrosis-related genes such as α-SMA, TGF-β1, and Col1a1. In a mouse experiment, CTGF was up-regulated in the liver 3 weeks after bile duct ligation (BDL). CTGF expression levels showed positive correlation with those of other fibrosis-related genes listed above. Immunochemistry of CTGF after BDL showed positive reaction both in parenchymal cells (PC) and non-parenchymal cells (NPC). Thus, we subsequently isolated PC and NPC from mice underwent BDL or sham, and compared respective CTGF expression levels between BDL and sham groups. CTGF was up-regulated both in PC and NPC in BDL groups. In vitro experiments revealed that treatment of TGF-β, an inducing factor of CTGF, increased CTGF expression and secretion not only in hepatocyte cell lines, Huh7 and PLC/PRF/5 cells but in hepatic stellate cell (HSC) cell lines, LX-2 cells. These findings indicated that both hepatocytes and HSC produce CTGF under the stimulation of BDL. We finally analyzed the potential of CTGF as a therapeutic target in liver fibrosis. In vitro CTGF treatment induced the activation and collagen production in LX-2 cells, suggesting CTGF has a promoting effect for liver fibrosis. We subsequently evaluated the degree of fibrosis after BDL in 3 strains of conditional CTGF knockout mice; HSC-specific CTGF deficient mice (GFAP-Cre+ CTGF flox/flox mice; CTGFΔHSC mice), hepatocyte-specific CTGF deficient mice (Alb-Cre+ CTGF flox/flox mice; CTGFΔHep mice), and poly IC-induced PC and NPC CTGF deficient mice (MX1-Cre+ CTGF flox/flox mice; CTG- FΔPC+NPC mice). As a result, compared with Cre- littermates, CTGF expression levels in the liver were significantly reduced to 55.8% and 27.7% in CTGFΔHep and ΔPC+NPC mice, respectively. No difference was observed in CTGFΔHSC mice. Liver fibrosis was attenuated only in CTGFΔPC+NPC mice, evidenced by reduced Collagen expression and Sirius Red-stained area. Conclusion: CTGF is produced from both PC and NPC and promotes hepatic fibrosis. CTGF is a promising therapeutic target in liver fibrosis. Disclosures: Hayato Hikita - Grant/Research Support: Bristol-Myers Squibb Tetsuo Takehara - Grant/Research Support: Chugai Pharmaceutical Co., MSD K.K., Bristol-Meyer Squibb, Mitsubishi Tanabe Pharma Corparation, Toray Industories Inc. ; Speaking and Teaching: MSD K.K., Bristol-Meyer Squibb, Janssen Pharmaceutical Companies The following authors have nothing to disclose: Yuki Makino, Yugo Kai, Yasutoshi Nozaki, Tasuku Nakabori, Yoshinobu Saito, Satoshi Tanaka, Ryotaro Sakamori, Naoki Hiramatsu, Tomohide Tatsumi 1358 Exosome-mediated activation of TLR3 in stellate cells stimulates IL-17A production of γδ T cells in liver fibrosis of mice Wonhyo Seo, Hyuk-Soo Eun, So Yeon Kim, Seol-Hee Park, Jong- Min Jeong, Won-Mook Choi, Myung-Ho Kim, Won-IL Jeong; KAIST, Daejeon, Korea (the Republic of) Background: During liver injury, hepatocytes secrete numerous exosomes including diverse types of self-RNAs. Recently, self-noncoding RNA has been considered as an activator to tolllike receptor 3 (TLR3). However, the roles of hepatic exosome and its detection by TLR3 have not been fully understood in the pathogenesis of liver fibrosis. In the present study, we identified that exosome-induced activation of TLR3 in hepatic stellate cells (HSCs) stimulated production of interleukin-17A (IL-17A) in γδ T cells, subsequently leading to acceleration of liver fibrosis in mice. Methods: Liver injury and fibrosis was induced with single or 2-week injection of carbon tetrachloride (CCl 4 ) in wild type (WT) and TLR3-deficient (TLR3 -/- ) mice. Liver immune cells, HSCs and hepatocytes were freshly isolated for flow cytometry and in vitro experiments. Results: In acute and chronic liver injuries, increased IL-17A production was mainly detected in hepatic γδ T cells of WT mice, whereas those of TLR3 -/- mice did not show any increase of IL-17A production in both liver injuries. In addition, liver fibrosis of TLR3 -/- mice was significantly attenuated compared with WT mice. More interestingly, IL-17A producing γδ T cells were in close contact with activated HSCs, suggesting implication of HSCs and TLR3 in IL-17A production of γδ T cells. Furthermore, in vitro treatments of exosomes derived from CCl 4 - or ethanol-treated hepatocytes significantly increased expression of IL-1β, IL-23 and IL-17A in HSCs, and remarkable increase of IL-17A production in γδ T cells was observed as they were co-cultured with exosome-treated WT HSCs or conditioned medium from TLR3-activated WT HSCs. However, all these finding were not detected as γδ T cells were co-cultured with exosome-treated HSCs of IL-17A -/- or TLR3 - /- mice. Using reciprocal bone marrow transplantation of WT and TLR3 -/- mice, we demonstrated TLR3 deficiency in HSCs contributed to decreased liver fibrosis and IL-17A production in γδ T cells. Conclusion: In liver injury, exosome-mediated activation of TLR3 in HSCs accelerates liver fibrosis by enhancing IL-17A production of γδ T cells, which might be associated with IL-17A production of HSCs by unknown self-TLR3 ligands
HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 877A released from damaged hepatocytes. Therefore, TLR3 might be a novel therapeutic target for liver fibrosis. Disclosures: The following authors have nothing to disclose: Wonhyo Seo, Hyuk-Soo Eun, So Yeon Kim, Seol-Hee Park, Jong-Min Jeong, Won-Mook Choi, Myung-Ho Kim, Won-IL Jeong Effects of ASK1 inhibitors on fatty acid metabolism 1359 Efficacy of an ASK1 Inhibitor to Reduce Fibrosis and Steatosis in a Murine Model of NASH is Associated with Normalization of Lipids and Hepatic Gene Expression and a Reduction in Serum Biomarkers of Inflammation and Fibrosis Satyajit Karnik 1 , Michael R. Charlton 2 , Li Li 1 , Michelle Nash 1 , Maisoun Sulfab 1 , David Newstrom 1 , Erik G. Huntzicker 1 , Dorothy French 1 , Zachary D. Goodman 3 , Tracy Shafizadeh 4 , Steve Watkins 4 , David Breckenridge 1 , Daniel Tumas 1 ; 1 Biology Research, Gilead Sciences, Foster City, CA; 2 Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN; 3 Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, VA; 4 Metabolon Inc, West Sacramento, CA BACKGROUND & SIGNIFICANCE: ASK1 is a kinase that is activated by various stimuli including oxidative stress, TGF-β, and hyperglycemia. ASK1 induces apoptosis, fibrosis, and metabolic dysfunction by activating p38 and JNK1. We previously demonstrated that ASK1 inhibition is efficacious in preclinical models of NASH and liver fibrosis. GS-4997, a first-in-class, oral small molecule ASK1 inhibitor, is being investigated in a Phase 2 clinical trial in NASH. Here, we further characterize the efficacy of ASK1 inhibition in a murine model of NASH by evaluating hepatic gene expression, hepatic and serum lipids, and serum biomarkers and cytokines. METHODS: NASH was induced in male C57BL/6 mice by administration of a diet high in fat, cholesterol, and sugar for 240 days. Animals were subsequently treated with either placebo or a selective, small molecule inhibitor of ASK1 for 90 days (n=15/group). Endpoints included steatosis evaluated by morphometry, clinical pathology, liver hydroxyproline levels, liver and plasma lipids by chromatography, hepatic gene expression by microarray, serum levels cytokines and fibrosis biomarkers by Luminex and ELISA. RESULTS: ASK1 inhibition reduced hepatic fibrosis, steatosis, and insulin resistance. ASK1 inhibitor treated animals had increased lipid metabolism and decreased de novo lipogenesis vs. controls as evaluated by lipid profiling in liver. ASK1 inhibitor treated animals had a 26% decrease in lipogenesis, a 21% decrease in stearoyl-CoA desaturase, and a 78% increase in delta-5 desaturase relative to placebo controls as reflected in the plasma lipidome (Table). Consistent with these effects, gene networks regulating fatty acid synthesis, lipid metabolism, and cholesterol biosynthesis were differentially expressed in ASK1 inhibitor treated animals vs. placebo controls. Serum levels of IL-6, and the fibrosis markers osteopontin, hyaluronic acid, and TIMP-1 were reduced by 50%, 35%, 33% and 41%, respectively, in ASK1 inhibitor treated animals vs. controls. CONCLUSIONS: The therapeutic benefit of an ASK1 inhibitor in reducing hepatic steatosis and fibrosis was associated with normalization of fatty acid synthesis and lipid metabolism. These data enhance our understanding of the mechanisms of action of ASK1 inhibition and further support evaluation of the ASK1 inhibitor, GS-4997, in patients with NASH. Disclosures: Satyajit Karnik - Consulting: Monsoon Dx; Employment: Gilead Sciences Michael R. Charlton - Grant/Research Support: GIlead Sciences, Merck, Janssen, AbbVie, Novartis Li Li - Employment: Gilead Sciences Michelle Nash - Employment: Gilead Sciences Erik G. Huntzicker - Employment: Gilead Sciences; Stock Shareholder: Gilead Sciences Dorothy French - Employment: Gilead Sciences; Stock Shareholder: Genentech - Roche Zachary D. Goodman - Consulting: Gilead Sciences, Abbvie; Grant/Research Support: Gilead Sciences, Fibrogen, Galectin Therapeutics, Intercept, Synageva, Conatus, Tobira, Exalenz David Breckenridge - Employment: Gilead Sciences Daniel Tumas - Employment: Gilead Sciences, Inc The following authors have nothing to disclose: Maisoun Sulfab, David Newstrom, Tracy Shafizadeh, Steve Watkins 1360 Endothelial Niche Derived Notch Signaling Pathway Balanced Liver Regeneration and Fibrosis in Distinct Ways Lin Wang; Hepatic Surgery, Fourth Military Medical University, Xi`an, China Abstract: Traumatic or toxic damage to the liver is often associated with liver regeneration and fibrosis. Liver sinusoidal endothelial niche has been addressed to modulate liver regeneration and fibrosis. Previously we found, Notch signaling was involved into the determination of liver sinusoidal endothelial cell (SEC) proliferation and differentiation by an angiocrine manner, and consequently influenced liver regeneration. However, the specific modulations and cell communications by endothelial niche-derived Notch signaling on liver reconstruction are still unknown. In this study, by using endothelial specific Notch Intracellular Domain (NICD) activated transgenic models (VeCad-CreERT-NICD) to persistently activate Notch signal, we firstly found SEC fenestration and sieve plates dramatically decreased both in vivo and in vitro. Meanwhile, sinusoidal perfusion and SEC endocytosis ability were significantly compromised compared to the control. Intriguingly, incapable hepatocyte proliferation, activated hepatic stellate cells (HSC) and liver malfunction were more remarkable in VeCad-CreERT-NICD mice. In 70% hepatectomy models, hepatocyte regeneration was largely blocked by NICD activation. By contrast, hepatic fibrosis induced by CCl 4 injection was apparently aggravated in Notch activated models. Excitingly, in different co-culture systems, isolated primary SEC with loss of fenestrations by Notch activation disrupted wild type hepatocyte proliferation, but initiated HSC activation. To illustrate the underlying mechanisms, we detected Wnt2, which was considered as a mitogen of hepatocytes, was downregulated in VeCad-CreERT-NICD SEC. Overexpression of Wnt2 successfully restored incapable hepatocyte proliferation in Notch activated mice. Besides, prominently increased ET1 was noticed in Notch activated SEC and potentially accelerated liver fibrosis in a Notch-ET1 dependent manner. Conclusion: We demonstrated Notch signal as a bi-directional switch in balancing hepatic regeneration and fibrosis through sinusoidal endothelial niche derived pro-regenerative Notch-Wnt2 versus pro-fibrotic Notch-ET1 pathways.
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1312A AUTHOR INDEX HEPATOLOGY, Octo
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