THU-467 Expression of the chemokine CCL24 and its receptor in the sera and livers of patients with non-alcoholic fatty liver disease Y. Maor 1 , D. Haberman 2 , M. Segal 3 , A. Katav 3 , S. Hashmueli 3 , J. George 4 , A. Mor 3 . 1 Kaplan Medical Center, Institute of Gastroenterology and Hepatology, Rehovot, Israel; 2 Kaplan Medical Center, Heart Center, Rehovot, Israel; 3 Chemomab, LTD; 4 Kaplan Medical Center, Heart Center Email: halish@netvision.net.il Background and Aims: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. Inflammation and fibrosis are the key pathological processes involved in the progression of NAFLD to non-alcoholic steatohepatitis (NASH). Chemokines play an important role in inducing inflammation and fibrosis and were found to be central in NASH progression. CCL24, a pro-inflammatory and pro-fibrotic chemokine, was recently found to be involved in the progression of inflammatory and fibrotic diseases and is tested for its involvement in NASH. Our aimwas to study the levels of circulating CCL24 and its receptor-CCR3 in NAFLD patients’ serum samples and liver biopsies and the association with its clinical features. Method: Serum samples from NAFLD patients were analyzed for CCL24 levels using commercial ELISA kit (R&D systems). CCR3 levels in peripheral blood mononuclear cells were tested by flow cytometry. Immunohistochemistry staining was performed to evaluate CCL24 and CCR3 in liver biopsies. Results: Our finding revealed significant elevation of CCL24 serum levels in NAFLD patients compared to healthy volunteers (718 ± 78 and 476 ± 36 pg/ml, respecitively, p  0.01). Moreover, we used Fib4 score to divide the NAFLD population to subgroups according to disease progression. We found that CCL24 levels were increased by ∼2 fold in high NAFLD Fib4 score patients (n = 23) compare to healthy volunteers (n = 20) (p  0.01) and by 1.5 fold compare to low Fib4 score NAFLD patients (n = 28) (p  0.05). CCL24 activity is mediated by its binding to its cognate receptor, CCR3. Thus, we assessed the levels of CCR3 expression in peripheral blood mononuclear cells isolated from NAFLD patients (n = 35) and healthy volunteers (n = 16). We found that CCR3 was significantly overexpressed in mononuclear cells isolated from NAFLD patients compared to healthy volunteers (3.81 ± 0.16% and 0.84 ± 0.1%, respectively, p  0.01). Significantly higher hepatic expression of CCL24 and CCR3 using immunohisto- chemistry was revealed in NASH patients’ liver biopsies with NAFLD Activity Score equal and higher than 5 compared with normal livers. Importantly (p  0.01, p  0.05, respectively). Conclusion: This is the first evidence, that the chemokine CCL24 and its cognate receptor, CCR3, are significantly increased in NAFLD patients both in the circulation and in the liver. These results may indicate a potential involvement of CCL24-CCR3 axis in the pathogenesis of NASH, thus suggesting that CCL24 may serve as a potential prognostic tool and a therapeutic target for the treatment of patients with NASH. THU-468 LJN452 (tropifexor) attenuates steatohepatitis, inflammation, and fibrosis in dietary mouse models of nonalcoholic steatohepatitis B. Laffitte 1 , E. Hernandez 1 , Y. Kim 1 , B. Liu 1 , P. Rucker 1 , D. Chianelli 1 , D. Bao 2 , J. Zoll 1 , J. Xu 1 , V. Molteni 1 , P. Mcnamara 1 , M. Badman 2 . 1 Genomics Institute of the Novartis Research Foundation, La Jolla, United States; 2 Novartis Institutes for BioMedical Research, Cambridge, United States Email: blaffitte@gnf.org Background and Aims: Farnesoid X receptor (FXR) agonists are investigational agents for the treatment of nonalcoholic steatohepa- titis (NASH) and other chronic liver diseases. The bile acid-derived FXR agonist obeticholic acid (OCA) demonstrated efficacy in Phase II NASH trials, but also caused cholesterol elevation and pruritus. LJN452 is a highly potent non-bile acid agonist currently under Phase II development. Here, we compare the efficacy of LJN452 and OCA in two mouse models of NASH. Method: STAM Model: Streptozotocin-injected 2-day old C57Bl/6J mice were placed on high-fat diet for weeks 4–12. From Week 9, mice received oral doses of LJN452 (0.03–0.3 mg/kg), OCA (25 mg/kg), or vehicle. Hematoxylin & eosin (H&E)-stained liver sections were assessed for nonalcoholic fatty liver disease activity score (NAS). Collagen deposition (fibrosis marker) was estimated by percent of Sirius-red positive area. AMLN Model: C57Bl/6 mice were placed on high fat (40% kcal), fructose (22% by wt), and cholesterol (2% by wt) diet for 30 weeks. LJN452 (0.03–0.9 mg/kg), OCA (25 mg/kg), or vehicle was orally dosed for the last 4 weeks. Treatment effects were monitored by histopathology (H&E, Trichrome and IBA1 staining) and assessment of liver-damage markers (alanine/aspartate aminotransferases [ALT/ AST]) levels and collagen type I, alpha1 (Col1a1) and tissue inhibitor of metalloproteinase 1 (TIMP1) mRNA levels. Results: Compared with normal mice, STAM mice showed marked increases in NAS and fibrotic area. LJN452 treatment showed significant decrease in NAS at doses ≥0.1 mg/kg ( p < 0.0001), whereas the effect of OCA tended was less marked. Significant dose- dependent reduction of Sirius Red-positive areas was observed with LJN452 (p < 0.001). In the AMLN model, LJN452, but not OCA, showed dose-dependent reduction in ALT/AST levels relative to controls. In addition, LJN452 reduced inflammation, steatosis, and fibrosis in AMLN mice. Steatosis and inflammation were completely resolved at LJN452 doses ≥0.3 mg/kg. LJN452 also dramatically reduced mRNA levels of fibrogenic markers Col1a1 and TIMP1. NASH mice exhibited hepatic inflammation as confirmed by IBA1+ staining of macrophages and Kupffer cells, which was dose-dependently reduced in LJN452- treated, but not OCA-treated, mouse livers. Conclusion: Marked improvement in NASH endpoints with LJN452 in two distinct models suggests its potential as a treatment for NASH and warrants its further clinical investigation in NASH patients. THU-469 EDP-305 modulates lipoprotein metabolism via distinct chromatin and microRNA regulatory mechanisms M. Roqueta-Riverta 1 , M. Chau 1 , K. Garlick 1 , Y. Li 2 , Y.S. Or 3 , L. Jiang 4 . 1 Enanta Pharmaceuticals, Inc., Biology, Watertown, United States; 2 Enanta Pharmaceuticals, Inc., Pharmacology, Watertown, United States; 3 Enanta Pharmaceuticals, Watertown, United States; 4 Enanta Pharmaceuticals, Inc, Pharmacology, Watertown, United States Email: ljiang@enanta.com Background and Aims: The Farnesoid X Receptor (FXR) has emerged as an attractive target for the treatment of NASH. EDP-305, a selective and potent small molecule FXR agonist, is currently being developed for the treatment of NASH. We previously demonstrated EDP-305 treatment results in different gene regulatory effects on lipoprotein metabolism (LDLR, SRB1) when compared to obeticholic acid (OCA). In this study, we sought to characterize transcriptional and post- transcriptional regulatory mechanisms by which EDP-305 regulates LDLR and SRB1 expression. Method: To examine the regulatory mechanisms of EDP-305 and OCA independent of drug potency, treatments were conducted near their respective EC 50 concentrations (EDP-305: 50 nM; OCA: 500 nM) in human hepatocytes (hepatoma, HepaRG). In vivo, C57B6/J mice were treated daily by oral gavage for 5 days with EDP-305 (30mg/kg) or OCA (100 mg/kg). Sonicated hepatocyte chromatin (∼500 bp) was used for chromatin immunoprecipitation (ChIP-qpCR) assays to measure histone methylation and transcription factor enrichment at LDLR and SRB1 promoters. miRNAs were isolated using the miRNAeasy kit (Qiagen). Results: Under basal conditions, both in vitro and in vivo, EDP-305 exhibited higher LDLR and lower SRB1 expression relative to OCA, despite equivalent expression of the FXR target, SHP . Thus, EDP-305 may have distinct transcriptional and post-transcriptional regulatory POSTER PRESENTATIONS S341 Journal of Hepatology 2018 vol. 68 | S105–S364