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

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-downregulated 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.

BRD4 inhibition and FXR activation, individually beneficial in cholestasis, are antagonistic in combination

“…Hepatic mRNA levels of FXR , as shown previously ( 5 ), and BRD4 were significantly reduced in PBC patients compared with healthy individuals, whereas those of inflammatory genes, IL6 and IL6RA , and fibrotic genes, ACTA2 and COL1A1 , were all substantially elevated in the patients ( Figure 8, A and B ). In previous studies, hepatic mRNA and protein levels of SHP, a target of FXR/BRD4, were not changed in patients with PBC compared with healthy subjects, but nuclear levels of SHP were substantially reduced in the patients ( 42 ). These results suggest that the FXR-BRD4 function is likely dysregulated in patients with PBC.…”

Total flavonoids of Astragalus Ameliorated Bile Acid Metabolism Dysfunction in Diabetes Mellitus

“…e negative feedback of bile acid hepatointestinal circulation is mediated by small molecule heterodimer partner (SHP), which is the downstream target of FXR [34]. It was found that the activation of FXR will induce SHP-inhibited expression of CYP7A1 and ASBT in liver cells [35,36]. Binding between SHP and transcription factor LRH-1 will regulate the expression of CYP7A1 in that LRH-1 inhibition will result in the decreased expression of CYP7A1 [37].…”

Integrated microRNA and proteome analysis reveal a regulatory module in hepatic lipid metabolism disorders in mice with subclinical hypothyroidism

“…In liver, miR-291b-3p promotes lipogenesis by suppressing AMPKα1 expression and activity (31). Hepatic miR-210 is elevated in cholestatic mice and PBC patients, promoting bile acids-induced liver injury by targeting mixed-lineage leukemia-4 (MLL4) (32). In the present study, it was observed that 8 (miR-10b-5p, miR-24-3p, miR-29a-3p, miR-30b-5p, miR-34a-5p, miR-125b-5p, miR-130a-5p and miR-199a-5p) out of these 17 miRNAs associated with hepatic lipid metabolic disorders were downregulated in the livers of SCH mice, suggesting that these miRNAs may be involved in hepatic lipid metabolic disorders in SCH.…”