Retinoid X receptor α in human liver is regulated by miR-34a

Retinoid X receptor a (RXR alpha) forms a heterodimer with numerous nuclear receptors to regulate drug- or lipid-metabolizing enzymes. In this study, we investigated whether human RXR alpha is regulated by microRNAs. Two potential recognition elements of miR-34a were identified in the RXR alpha mRNA: one in the coding region and the other in the 3'-untranslated region (3'-UTR). Luciferase assays revealed that miR-34a recognizes the element in the coding region. The overexpression of miR-34a in HepG2 cells significantly decreased the endogenous RXR alpha protein and mRNA levels. The stability of RXR alpha mRNA was decreased by the overexpression of miR-34a, indicating that miR-34a negatively regulates RXR alpha expression by facilitating mRNA degradation. We found that the miR-34a-dependent down-regulation of RXR alpha decreases the induction of CYP26 and the transactivity of CYP3A4. miR-34a has been reported to be up-regulated by p53, which has an ability to promote liver fibrosis. The p53 activation resulted in an increase of the miR-34a level and a decrease of the RXR alpha protein level. In addition, the miR-34a levels in eight fibrotic livers were higher than those in six normal livers, and the reverse trend was found for the RXR alpha protein levels. An inverse correlation was observed between the miR-34a and the RXR alpha protein levels in the 14 samples. Taken together, the data show that miR-34a negatively regulates RXR alpha expression in human liver, and affects the expression of its downstream genes. This miR-34a-dependent regulation might be the underlying mechanism responsible for the decreased expression of the RXR alpha protein in fibrotic livers. (c) 2014 Elsevier Inc. All rights reserved.