microRNAs in lipoprotein metabolism and cardiometabolic disorders

Abstract

Circulating levels of low-density lipoprotein cholesterol (LDL), and high-density lipoprotein cholesterol (HDL) are two of the most important risk factors for the development of cardiovascular disease (CVD), the leading cause of death worldwide. Recently, miRNAs have emerged as critical regulators of cholesterol metabolism and promising therapeutic targets for the treatment of CVD. A great deal of work has established numerous miRNAs as important regulators of HDL metabolism. This includes miRNAs that target ABCA1, a critical factor for HDL biogenesis and reverse cholesterol transport (RCT), the process through which cells, including arterial macrophages, efflux cellular cholesterol for transport to and removal by the liver. The most well studied of these miRNAs, miR-33, has been demonstrated to target ABCA1, as well as numerous other genes involved in metabolic function and RCT, and therapeutic inhibition of miR-33 was found to increase HDL levels in mice and non-human primates. Moreover, numerous studies have demonstrated the beneficial effects of miR-33 inhibition or knockout on reducing atherosclerotic plaque burden. Even more recent work has identified miRNAs that regulate LDL cholesterol levels, including direct modulation of LDL uptake in the liver through targeting of the LDL receptor. Among these, inhibition of miR-128-1, miR-148a, or miR-185 was found to reduce plasma LDL levels, and inhibition of miR-185 was further demonstrated to reduce atherosclerotic plaque size in ApoE(-/-) mice. Due to their ability to target many different genes, miRNAs have the ability to mediate complex physiologic changes through simultaneous regulation of multiple interrelated pathways. Of particular importance for CVD, inhibition of miR-148a may prove an important therapeutic approach for combating dyslipidemia, as this has been demonstrated to both raise plasma HDL levels and lower LDL levels in mice by targeting both ABCA1 and LDLR, respectively. In this review we highlight recent advances in our understanding of how miRNAs regulate cholesterol metabolism and the development of atherosclerotic plaques and discuss the potential of anti-miRNA therapies for the treatment and prevention of CVD.

Keywords: Atherosclerosis; Lipid metabolism; microRNAs.

Figure 1. 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 [ABCA1 and ABCG1 (only in rodents)] and bile acid synthesis (CYP7A1) and secretion (ABCB11 and ATP8B1). In addition to miR-33, ABCA1 is highly regulated at the post-transcriptional level in several tissues by numerous miRNAs including miR-33, miR-148a, miR-144, miR-758, miR-128a, miR-27a/b, miR-26 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, miR-96.

Figure 2. Role of miR-33 in regulating macrophage functions

miR-33 controls numerous macrophage functions by regulating the expression of genes associated with cholesterol efflux (ABCA1 and ABCG1), mitochondrial biogenesis (PGC-1α, PDK4 and SLC25A25) and macrophage polarization (AMPK).

Figure 3. miRNA regulation of LDL-C metabolism

The liver plays a key role in controlling plasma LDL-C levels by regulating VLDL secretion and LDL clearance via the LDLR. VLDL secretion is regulated by microsomal transfer protein (MTP). MTP expression is controlled by miR-30c and miR-122. LDLR and LDLRAP1 hepatic levels are regulated by numerous miRNAs including miR-301b, miR-130b, miR-185, miR-128-1, miR-148a and miR-27a/b.