Animals were sacrificed at 9 weeks of age, and biochemical, gene expression, and histologic evaluations of the liver were conducted. Results: CVC treatment had no effect on body or Pirfenidone in vitro liver weight, whole blood glucose, or liver triglycerides. Mean

(±SD) alanine aminotransferase levels were significantly decreased in both CVC treatment groups compared to control (58±12, 51 ±13 and 133±80 U/L for low dose, high dose and vehicle, respectively; p < 0.05). By real-time RT-PCR, collagen type 1 mRNA in whole liver lysates decreased by 27-37% with CVC treatment. The percentage of fibrosis area (by Sirius red staining) was significantly decreased by CVC treatment (p < 0.01). Importantly, the histologic non-alcoholic fatty liver disease activity score (score is 0 for untreated mice in this model) was significantly decreased with CVC treatment (4.0 ± 0.6, 3.7 ± 0.8 and 5.3 ± 0.5 for low dose, high dose and vehicle, respectively; p < 0.05), primarily due to reduced inflammation and ballooning scores. As previously shown in man, a CVC dose related increase

in plasma monocyte chemotactic protein-1 levels was observed in mice (1.1- and 1.5-fold increase for low and high MG-132 molecular weight dose, respectively), consistent with antagonism of CCR2.Conclusions: These data suggest that CVC, an investigational agent currently in human trials for HIV-1, has anti-fibrotic and anti-inflammatory activity in a mouse model of NASH, warranting further investigation. These findings provide further evidence that disrupting the CCR2/monocyte chemotactic protein-1 axis may be a novel treatment approach for NASH. Disclosures: Eric Lefebvre – Employment: Tobira Therapeutics Inc., San Francisco, CA, USA Taishi Hashiguchi – Employment: Stelic Institute & Co. Helen Jenkins – Employment: Tobira Therapeutics, Inc. Antoun Nabhan – Management Position: Tobira Therapeutics, Inc. Hiroyuki Yoneyama enough – Management Position: Stelic Institute & Co. Scott L. Friedman – Advisory Committees or Review Panels: Pfizer Pharmaceutical,

Sanofi-Aventis; Consulting: Abbott Laboratories, Conatus Pharm, Exalenz, Genenetch, Glaxo Smith Kline, Hoffman-La Roche, Intercept Pharma, Isis Pharmaceuticals, Melior Discovery, Nitto Denko Corp., Debio Pharm, Synageva, Gilead Pharm., Ironwood Pharma, Alnylam Pharm, Tokai Pharmaceuticals, Bristol Myers Squibb, Takeda Pharmaceuticals, Nimbus Discovery, Isis Pharmaceuticals; Grant/Research Support: Galectin Therapeutics, Tobira Pharm, Vaccinex Therapeutics; Stock Shareholder: Angion Biomedica Grushenka H. Wolfgang – Consulting: Tobira Therapeutics “
“Chronic cholangiopathies have limited therapeutic options and represent an important indication for liver transplantation. The nuclear farnesoid X receptor (FXR) and the membrane G protein-coupled receptor, TGR5, regulate bile acid (BA) homeostasis and inflammation.