A novel diet-induced murine model of steatohepatitis with fibrosis for screening and evaluation of drug candidates for nonalcoholic steatohepatitis.

Abstract

Many animal models of nonalcoholic steatohepatitis have been reported. While these models exhibit mild onset of hepatitis and fibrosis, induction is often slow. For faster screening of drug candidates, there is a compelling need for convenient animal models of steatohepatitis and nonalcoholic steatohepatitis in which fatty liver and hepatitis are stably induced within a short period. Here, we analyzed the hepatic lipid composition in nonalcoholic steatohepatitis, and used this information to successfully establish a murine model where steatohepatitis is induced within only 1 week using a novel diet (steatohepatitis‐inducing high‐fat diet, STHD‐01) high in saturated fatty acids and cholesterol. After receiving STHD‐01 for 1 week, normal mice (C57BL/6J) showed elevated markers of fatty liver and hepatitis, including hepatic triglycerides and plasma alanine aminotransferase; the administration of angiotensin receptor blockers reduced these symptoms. Furthermore, we confirmed that STHD‐01 administration for 36 weeks induced not only sustained elevation of hepatic triglyceride and plasma alanine aminotransferase levels, but also fibrosis and tumor formation. Pretreatment with the carcinogen diethylnitrosamine accelerated tumor formation, and hepatic lesions were observed within 30 weeks of STHD‐01 feeding following diethylnitrosamine pretreatment. Finally, branched‐chain amino acids, known to reduce the risk for hepatocellular carcinoma in preclinical models, were effective in reducing the progression of liver fibrosis induced by STHD‐01 feeding after diethylnitrosamine pretreatment. We concluded that STHD‐01 administration successfully induces steatohepatitis within a short period of time. The proposed murine model is suitable for studying the long‐term effects of pharmaceutical agents targeting steatohepatitis, fibrosis, and tumor formation.