MicroRNA-1 and microRNA-206 suppress LXRα-induced lipogenesis in hepatocytes

Liver X receptor alpha (LXR alpha) plays a critical role in the transcriptional control of lipid metabolism. LXR activation induces the expression of lipogenic genes, which promote hepatic steatosis and steatohepatitis. However, the regulation of LXR is not fully understood. MicroRNAs (miRs) are regarded as important negative regulators of gene expression. In this study, we found that miR-1/miR-206 repressed LXR alpha-induced accumulation of lipid droplets in hepatocytes. In addition, bioinformatic analysis predicted a same putative target-site for miR-1/miR-206 located within the 3'-untranslated region (3'-UTR) of LXRa mRNA. The reporter assay revealed that miR-1/miR-206 directly targeted the 3'-UTR of LXRa. mRNA. Furthermore, miR-1/miR-206 repressed LXRa expression at both mRNA and protein levels, accompanied with the inhibition of expression of LXRa target genes, such as sterol-regulatory element binding protein 1c, fatty acid synthase, carbohydrate responsive element-binding protein and acetyl-CoA carboxylase 1, which are important effectors of LXRa implicated in lipogenesis. Moreover, ectopic expression of LXRa without the 3'-UTR dramatically attenuated the miR-1/miR-206-induced decrease of lipogenic genes and lipid droplet accumulation. Taken together, we for the first time demonstrated that miR-1/miR-206 attenuated LXRa-induced lipogenesis by targeting the 3'-UTR of LXR alpha mRNA, suggesting that miR-1/miR-206-LXR alpha pathway may be a novel target for the treatment of lipogenesis-associated diseases. (C) 2013 Elsevier Inc. All rights reserved.