MicroRNAs in lipid metabolism

Abstract

Purpose of review: Although the role for microRNAs (miRNAs) in regulating multiple physiological processes including apoptosis, cell differentiation, and cancer is well established, the importance of these tiny RNAs in regulating lipid metabolism has only recently been uncovered. This review summarizes the evidence for a critical role of miRNAs in regulating lipid metabolism.

Recent findings: Lipid metabolism is tightly regulated at the cellular level. In addition to classic transcriptional regulation of cholesterol metabolism (e.g. by SREBP and LXR), members of a class of noncoding RNAs termed miRNAs have now been identified to be potent post-transcriptional regulators of lipid metabolism genes involved in cholesterol homeostasis and fatty acid oxidation. Several reports have recently shown that miR-33 regulates cholesterol efflux and HDL biogenesis by downregulating the expression of the ABC transporters, ABCA1 and ABCG1. In addition, miR-33 also inhibits the translation of several transcripts encoding proteins involved in fatty acid β-oxidation including CPT1a, CROT, and HADHB, thereby reducing fatty acid degradation. Other miRNAs including miR-122, miR-370, miR-335, and miR-378/378*, miR-27 and miR-125a-5p have been implicated in regulating cholesterol homeostasis, fatty acid metabolism and lipogenesis.

Summary: Recent advances in the understanding of the regulation of lipid metabolism indicate that miRNAs play major roles in regulating cholesterol and fatty acid metabolism. These new findings may open new avenues for the treatment of dyslipidemias.

Figure 1. Gene regulatory network of lipid homeostasis

In cholesterol-depleted conditions, SREBP-2 is activated and enhances the expression of genes dedicated to the synthesis and uptake of cholesterol, as well as the NADPH cofactor required to synthesize these molecules. Similarly, SREBP-1a regulates cholesterol metabolism but its expression is relatively low in vivo. SREBP-1c is activated by liver X receptor (LXR) agonists (oxysterols) and insulin, and regulates the expression of genes required for fatty acid synthesis. In cholesterol saturating conditions, the oxidized cholesterol derivatives activate LXR leading to an increase of ABCA1 and ABCG1 expression and cellular cholesterol efflux.

Figure 2. miR-33 represses expression of genes involved in cholesterol export and fatty acid oxidation

Activation of Srebf-1 or Srebf-2 results in co-transcription of miR-33b and miR-33a, respectively. These miRNAs simultaneously inhibit the expression of genes involved in fatty acid metabolism (CROT, CPT1a, HADHB) and cholesterol transport (ABCA1, ABCG1, NPC1). The outcome of miR-33a/b activation is reduced fatty acid β-oxidation and decreased movement of cholesterol into the HDL pathway.