脂肪肝研究摘要easl.docVIP

PS066 FXR AGONISM BY GS-9674 DECREASES STEATOSIS AND FIBROSIS IN A MURINE MODEL OF NASH J.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, Heidelberg, Germany E-mail: John.Liles@G Background and Aims: GS-9674 is a selective nonsteroidal Farnesoid X Receptor (FXR) agonist being developed by Gilead Sciences for the treatment of NASH. FXR is a nuclear hormone receptor that is highly expressed in the gastrointestinal tract and liver, and is a primary regulator of bile acid (BA) homeostasis. GS-9674 acts in the intestine to produce FGF19 (FGF15 in rodents), an endocrine hormone that down-regulates BA synthesis, lipogenesis and gluconeogenesis in the liver and increases energy expenditure in adipose tissue. Both low FGF19 and high BA levels have been associated with the pathogenesis and progression of NASH including the degree of hepatic fibrosis. In this study we evaluated the therapeutic efficacy of GS-9674 in mice with established NASH. Methods:NASHwas induced in male C57BL/6 mice byadministration of a fast food diet (FFD) high in fat, cholesterol, 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 included steatosis evaluated by morphometry, liver hydroxyproline levels, clinical pathology, NAFLD activity scores (NAS) by histology, and an oral glucose tolerance test. C57BL/6 mice on a normal diet (n = 15/ group) were a control group. Results: Serum cholesterol, AST and ALT, and liver steatosis and fibrosis were significantly elevated in vehicle-treated mice following 240 and 330 days of FFD relative to control mice. Compared to vehicle-treated mice, mice treated with GS-9674 from day 240 to 330 demonstrated 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) and chole