Critical Role of Cholic Acid in the Development of iHFC Diet-induced MASH in TSNO Mice.

Abstract

A high-fat/cholesterol/cholate-based (iHFC) diet induces pathological changes in Tsumura-Suzuki non-obese (TSNO) mice, resembling human metabolic dysfunction associated steatohepatitis (MASH), along with advanced liver fibrosis. In this study, we investigated the role of cholic acid (CA) in the development of iHFC diet-induced MASH development. In mice receiving an iHFC diet without CA (CA(-) iHFC diet), both lobular inflammation and fibrosis progression in the liver were attenuated compared to those on the standard iHFC diet. Notably, hepatocyte ballooning was significantly improved in the CA(-) iHFC diet group. The expression levels of genes associated with inflammation and fibrosis were lower in the livers of CA(-) iHFC diet-fed mice compared to those fed the iHFC diet. Furthermore, there were no significant changes in the proportion and number of monocyte-derived macrophages in the livers of CA(-) iHFC diet-fed mice relative to those in the ND (normal diet)-fed group. The co-localization of CD11c⁺ macrophages with collagen fibers in the livers of CA(-) iHFC diet-fed mice did not significantly differ from that of the ND-fed group. Moreover, the CA(-) iHFC-fed mice exhibited a distinct microbial composition relative to both ND- and iHFC-fed mice. Finally, the increase in deoxycholic acid in fecal samples and the reduced hepatic expression of Cyp27a1 and Cyp7a1 induced by the iHFC diet were less in the CA(-) iHFC-fed group. These results suggest that CA modulates iHFC diet-induced MASH development by influencing the accumulation of monocyte-derived macrophages in the liver and shaping the gut microbiota composition and bile acid profile.