miRNA and cholesterol homeostasis

Abstract

MicroRNAs (miRNAs) have recently emerged as a novel class of epigenetic regulators of gene expression. They are systemically involved in the control of lipid metabolism through a complex interactive mechanism that involves gene regulatory networks. Hence, they can contribute to defective lipid metabolism and metabolic diseases. Here, we review recent advances in the roles of lipid-sensing transcription factors in regulating miRNA gene networks, as well as miRNA expression and function in the regulation of cholesterol metabolism. This article is part of a Special Issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernández-Hernando and Yajaira Suárez.

Keywords: Cholesterol metabolism; Metabolic disease; MicroRNA; Transcription factor.

Fig. 1

Transcription factors and miRNAs regulatory network in cholesterol homeostasis. a. SREBP-2 increased miR-183/96/182 cluster that targets INSIG2 and Fbxw7, constituting a positive-feedback loop to regulate SREBP activity. b. miR-33a/b locate within the introns of SREBP genes, and these transcripts coordinate to regulate cholesterol transport and synthesis/uptake to maintain cellular cholesterol homeostasis. c. LXR downregulates miR-26 that targets ABCA1 and ARL7, enhancing cholesterol transport, whereas miR-144 and miR613 are upregulated by LXR and target ABCA1 and LXR, suggesting the presence of negative-feedback regulation in the cholesterol efflux process. d. FXR-regulated miR-144 suppresses hepatic ABCA1 and plasma HDL-C levels, but increased hepatic SR-BI enhances biliary excretion in the RCT process. FXR also inhibits miR-34a through SHP activation that inactivates p53, which results in a positive regulation of SIRT1.