Altered bile acid composition and disposition in a mouse model of non-alcoholic steatohepatitis.

ABSTRACT

Non-alcoholic steatohepatitis (NASH) is a progressive inflammatory and fibrotic disease. However, the progression mechanism of NASH is not well understood. Bile acids are endogenous molecules that regulate cholesterol homeostasis, lipid solubilization in the intestinal lumen, and metabolic signaling via several receptors. In this study, we investigated the relationship between bile acid composition and NASH-associated fibrosis using a mouse model fed choline-deficient, L-amino-acid-defined, high-fat diet with 0.1% methionine (CDAHFD). C57BL/6 J mice fed CDAHFD developed NASH and fibrosis within few weeks. With the progress of NASH-associated liver fibrosis, altered bile acid composition was observed in the liver, bile, and peripheral plasma. Decreased mRNA levels of bile acid metabolizing enzymes such as Cyp7a1 and Baat were observed in contrast to increased Sult2a1 level in the liver. Increased mRNA levels of Ostß and Abcc4 and decreased in mRNA levels of Bsep, Abcc2, Ntcp, and Oatp1b2, suggesting that bile acids efflux from hepatocytes into the peripheral plasma rather than into bile. In conclusion, the changes in bile acid metabolizing enzymes and transporters expression, resulting in increasing the total bile acid concentration in the plasma, signify a protection mechanism by the hepatocyte to reduce hepatotoxicity during disease progression to NASH but may promote liver fibrosis.