Gly-βMCA modulates bile acid metabolism to reduce hepatobiliary injury in Mdr2 KO mice.

Abstract

Cholestasis results from impaired bile flow that causes hepatic bile acid accumulation and injury. Alleviating bile acid hepatobiliary toxicity is a major therapeutic goal in cholestasis. Our recent study revealed a potent anti-cholestasis effect of glycine-conjugated β-muricholic acid (Gly-βMCA) in Cyp2c70 KO mice with humanized hydrophobic bile acid composition. To better understand the mechanisms and human relevance of the therapeutic benefits of Gly-βMCA, we investigated the effects of Gly-βMCA on bile acid metabolism and biliary injury in Mdr2 KO mice, a cholestasis model with a hydrophilic murine bile acid composition. Gly-βMCA significantly reduced serum alkaline phosphatase (ALP), ductular reaction, and liver cytokine expression in female mice but offered little benefits in male mice. Consistently, Gly-βMCA reduced hepatic bile acids and total bile acid pool size in female but not male mice, due to its ability to promote fecal bile acid excretion. However, the endogenous taurine-conjugated MCA (T-MCA) limited the ability of Gly-βMCA to further enrich the bile acid pool with Gly-βMCA-derived T-MCA to reduce bile acid hydrophobicity. Overall, Gly-βMCA showed diminished therapeutic efficacy in Mdr2 KO mice than in Cyp2c70 KO mice, which may be due to differences in bile acid hydrophobicity and disease etiology in the two cholestasis models. These findings suggest that the benefits of Gly-βMCA are mediated by its unique pharmacokinetics that allows for simultaneous reduction of bile acid pool size and hydrophobicity. Gly-βMCA may be a promising therapy for treating human cholestasis, despite its reduced efficacy in improving the toxicity profile of murine bile acid pool.