MicroRNA hsa-miR-613 Targets the Human LXRα Gene and Mediates a Feedback Loop of LXRα Autoregulation

The nuclear receptor liver X receptor (LXR) is a ligand-dependent transcription factor that plays an important role in the metabolism and homeostasis of cholesterol, lipids, bile acids, and steroid hormones. MicroRNAs (miRNAs) are recently recognized important negative regulators of gene expression. In this report, we showed that miRNA hsa-miR-613 played an important role in the autoregulation of the human LXRα gene. hsa-miR-613 targeted the endogenous LXRα through its specific miRNA response element (613MRE) within the LXRα 3'-untranslated region. Interestingly and paradoxically, the expression of hsa-miR-613 itself was induced upon the activation of LXR. However, hsa-miR-613 did not appear to be a direct LXR target gene. Instead, the positive regulation of hsa-miR-613 by LXR was mediated by the sterol regulatory element binding protein (SREBP)-1c, a known LXR target gene. Promoter analysis revealed an SREBP response element in the hsa-miR-613 gene promoter. Treatment with insulin also induced the expression of hsa-miR-613 in an SREBP-1c-dependent manner, further supporting the role of SREBP-1c in the positive regulation of this miRNA species. Finally, the autoinduction of LXRα by a LXR agonist was enhanced when hsa-miR-613 was inhibited or SREBP-1c was down-regulated. hsa-miR-613 appeared to specifically target the human LXRα. We propose that the negative regulation mediated by hsa-miR-613 and SREBP-1c and the previously reported positive regulation mediated by an LXR response element in the LXRα gene promoter constitute a ying-yang mechanism to ensure a tight regulation of this nuclear receptor of many metabolic functions.