The Role of microRNAs in the Regulation of Human UDP-glucuronosyltransferases (UGTs)

Abstract

The liver is involved in endo- and xenobiotic metabolism due to the expression of drug-metabolizing UDP-glucuronosyltransferases (UGTs). By UGT-mediated elimination of hazardous compounds and other reactive metabolites, oxidative stress is reduced in the liver. The UGT1A family of proteins contain the common 3'-UTR that can be targeted by regulatory microRNAs. In this work, a variety of microRNAs dysregulated in hepatocellular carcinoma were tested in UGT1A 3'-UTR luciferase assays and overexpressed in HepG2, Kyse-70, and Caco-2 cells to evaluate a potential reduction in UGT1A mRNA and protein expression. Two microRNAs (miR-214-5p and miR-486-3p) were identified to target binding sites in the UGT1A 3'-UTR and thereby reduced luciferase assays, UGT1A mRNA, and protein levels. miR-486-3p was observed to be upregulated in the serum of cirrhotic patients and male fibrotic humanized transgenic UGT1A-wildtype mice. In conclusion, miR-486-3p is suggested to be a potential risk factor for the development or progression of liver fibrosis/cirrhosis due to reduced UGT1A-mediated glucuronidation activity towards reactive metabolites and the potential disruption of the metabolic antioxidative balance in the liver.