MicroRNA‐210 Promotes Bile Acid–Induced Cholestatic Liver Injury by Targeting Mixed‐Lineage Leukemia‐4 Methyltransferase in Mice

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Abstract
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.
Funding Information
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK62777, DK95842)
  • American Heart Association (16SDG27570006)

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