Background and Aims: Bile acids (BAs) are important regulators of metabolism and energy balance, but excess BAs cause cholestatic liver injury. The histone methyltransferase mixed-lineage leukemia-4 (MLL4) is a transcriptional coactivator of the BA-sensing nuclear receptor farnesoid X receptor (FXR) and epigenetically up-regulates FXR targets important for the regulation of BA levels, small heterodimer partner (SHP), and bile salt export pump (BSEP). MLL4 expression is aberrantly down-regulated and BA homeostasis is disrupted in cholestatic mice, but the underlying mechanisms are unclear. Approach and Results: We examined whether elevated microRNA-210 (miR-210) in cholestatic liver promotes BA-induced pathology by inhibiting MLL4 expression. miR-210 was the most highly elevated miR in hepatic SHP-down-regulated mice with elevated hepatic BA levels. MLL4 was identified as a direct target of miR-210, and overexpression of miR-210 inhibited MLL4 and, subsequently, BSEP and SHP expression, resulting in defective BA metabolism and hepatotoxicity with inflammation. miR-210 levels were elevated in cholestatic mouse models, and in vivo silencing of miR-210 ameliorated BA-induced liver pathology and decreased hydrophobic BA levels in an MLL4-dependent manner. In gene expression studies, SHP inhibited miR-210 expression by repressing a transcriptional activator, Kruppel-like factor-4 (KLF4). In patients with primary biliary cholangitis/cirrhosis (PBC), hepatic levels of miR-210 and KLF4 were highly elevated, whereas nuclear levels of SHP and MLL4 were reduced. Conclusions: Hepatic miR-210 is physiologically regulated by SHP but elevated in cholestatic mice and patients with PBC, promoting BA-induced liver injury in part by targeting MLL4. The miR-210–MLL4 axis is a potential target for the treatment of BA-associated hepatobiliary disease.
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