MicroRNAs and lipid metabolism

Abstract

Purpose of review: Work over the past decade has identified the important role of microRNAs (miRNAS) in regulating lipoprotein metabolism and associated disorders including metabolic syndrome, obesity, and atherosclerosis. This review summarizes the most recent findings in the field, highlighting the contribution of miRNAs in controlling LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C) metabolism.

Recent findings: A number of miRNAs have emerged as important regulators of lipid metabolism, including miR-122 and miR-33. Work over the past 2 years has identified additional functions of miR-33 including the regulation of macrophage activation and mitochondrial metabolism. Moreover, it has recently been shown that miR-33 regulates vascular homeostasis and cardiac adaptation in response to pressure overload. In addition to miR-33 and miR-122, recent GWAS have identified single-nucleotide polymorphisms in the proximity of miRNA genes associated with abnormal levels of circulating lipids in humans. Several of these miRNAs, such as miR-148a and miR-128-1, target important proteins that regulate cellular cholesterol metabolism, including the LDL receptor (LDLR) and the ATP-binding cassette A1 (ABCA1).

Summary: MicroRNAs have emerged as critical regulators of cholesterol metabolism and promising therapeutic targets for treating cardiometabolic disorders including atherosclerosis. Here, we discuss the recent findings in the field, highlighting the novel mechanisms by which miR-33 controls lipid metabolism and atherogenesis, and the identification of novel miRNAs that regulate LDL metabolism. Finally, we summarize the recent findings that identified miR-33 as an important noncoding RNA that controls cardiovascular homeostasis independent of its role in regulating lipid metabolism.

Figure. miRNA regulation of HDL-C metabolism

ABCA1, a major transporter that regulates HDL biogenesis and cholesterol efflux in macrophages accumulated in the artery wall, is regulated by a number of miRNAs including miR-33. miR-33 controls numerous steps of the reverse cholesterol transport pathway by regulating the expression of numerous genes associated with HDL biogenesis (ABCA1), cholesterol efflux in peripheral tissues including macrophages and cardiac fibroblasts [ABCA1 and ABCG1 (only in rodents)] and bile acid synthesis (CYP7A1) and secretion (ABCB11 and ATP8B1)in liver. In addition, miR-33 also promotes lipid accumulation in macrophages and favors Mtb survival by targeting the expression of key autophagy effectors ATG5, ATG7, ATG12, LAMP-1 and LIPA and controls macrophage polarization by regulating the expression of PRKAA1, AMPK and ALDH1A2. In addition to miR-33, ABCA1 is highly regulated at the post-transcriptional level in several tissues by numerous miRNAs including miR-148a, miR-144, miR-101, miR-128, miR-27a/b, miR-302a and miR-10b. Free cholesterol in nascent HDL is further esterified to cholesteryl esters by lecithin-cholesterol acyltransferase (LCAT) leading to the formation of mature HDL particles. HDL particles deliver cholesterol to the liver via the SRB1 receptor, which is also regulated by several miRNAs including miR-185, miR-223, and miR-96. This figure was performed using the Servier Medical Art illustration resources.