miR-141-3p commonly regulates human UGT1A isoforms via different mechanisms

UDP-Glucuronosyltransferase (UGT) 1A enzymes catalyze the glucuronidation of various compounds. Since no correlation was observed between the protein and mRNA expression of some UGT1A isoforms in the human liver, the involvement of post-transcriptional regulation was hypothesized. We examined whether microRNAs (miRNAs) regulate human UGT1A, focusing on the predicted miR-141-3p. A luciferase assay revealed that a miRNA recognition element for miR-141-3p in the 3'-untranslated region of UGT1A mRNA was functional. Overexpression of miR-141-3p in HEK293 cells stably expressing UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, or UGT1A9 significantly decreased the protein expression of all UGT1As. The mRNA levels of the UGT1As, except for UGT1A9, were also decreased by miR-141-3p. This indicated that the regulation mechanisms by miR-141-3p were different between UGT1A9 and the other UGT1A isoforms. Overexpression of miR-141-3p in HuH-7 or Caco-2 cells significantly decreased 4-methylumbelliferone O-glucuronosyltransferase activities, suggesting that miR-141-3p down-regulates endogenous UGT1As. No correlation was observed between miR-141-3p and the UGT1A mRNA levels in a panel of human liver samples, suggesting that regulation by other factors could hide the contribution of miR-141-3p to the regulation of UGT1A constitutive expression in the human liver. In conclusion, this study revealed that the miR-141-3p is an additional modulator of human UGT1A expression.