Disclosures: Michael L. McCaleb – Employment: Isis Pharmaceuticals; Stock Shareholder:

Isis Pharmaceuticals Jeff R. Crosby- Employment: ISIS Pharmaceuticals Detlef Schuppan – Advisory Committees find more or Review Panels: Aegerion, Eli Lilly, Gilead; Consulting: Boehringer-Ingelheim, Isis, Takeda; Grant/Research Support: Boehringer-Ingelheim The following people have nothing to disclose: Shih-Yen Weng, Kornelius Padberg, Yong Ook Kim, Xiao-Yu Wang Background and Aim: Branched-chain amino acids (BCAAs) reportedly improve event-free survival in patients with liver cirrhosis and inhibit liver carcinogenesis in heavier patients with liver cirrhosis. However, the mechanisms underlying these effects remain unclear. The aim of this study was to determine the effect of BCAAs on liver steatosis, fibrosis, and tumorigenesis in mice fed an atherogenic high-fat

(Ath HF) diet. Methods: Male mice (8 weeks old) were divided into 3 groups, and Dabrafenib ic50 each group was fed one of the following diets for 12, 30, or 60 weeks: basal diet, Ath HF diet, and Ath HF diet containing 3% BCAAs. The degree of hepatic steatosis and fibrosis and tumor number were calculated. The expression of fibrosis-related genes was evaluated by immunohistochemical staining, realtime polymerase chain reaction, and Western blotting. Lx2 cells activated by recombinant MCE公司 TGF-β were treated with BCAAs or transfected with Raptor siRNA to examine the mechanisms underlying the effects of BCAAs. Results: Mice fed the Ath HF diet for 12 or 30 weeks developed liver steatosis and fibrosis, whereas mice fed the Ath HF diet containing BCAAs showed markedly reduced steatosis and fibrosis. The expression of collagen I/IV, αSMA, TGF-β, PDGFR-β, and pERK was suppressed in mice fed the Ath HF diet containing BCAAs compared with mice fed only the Ath HF diet. After 60 weeks, 71 % of mice fed the Ath HF diet developed

liver tumors. BCAAs reduced tumor incidence to 25%. In Lx-2 cells, recombinant TGF-β induced the expression of collagen I, PDGFR-β, and pERK, whereas BCAAs suppressed the expression of these genes in a dose-dependent manner. In Lx-2 cells transfected with Raptor siRNA, the expression of collagen I and PDGFR-β was increased. Conclusions: BCAAs improved liver fibrosis and reduced tumorigenesis in mice fed the Ath HF diet, possibly by suppressing PDGFR-β/ERK signaling. We believe these findings may have a significant therapeutic impact on nonalcoholic steatohepatitis. Disclosures: Shuichi Kaneko – Grant/Research Support: MDS, Co., Inc, Chugai Pharma., Co., Inc, Toray Co., Inc, Daiichi Sankyo., Co., Inc, Dainippon Sumitomo, Co., Inc, Aji-nomoto Co., Inc, MDS, Co., Inc, Chugai Pharma., Co., Inc, Toray Co., Inc, Daiichi Sankyo., Co.