MicroRNA regulation of cholesterol metabolism

Abstract

MicroRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level. Since many microRNAs have multiple mRNA targets, they are uniquely positioned to regulate the expression of several molecules and pathways simultaneously. For example, the multiple stages of cholesterol metabolism are heavily influenced by microRNA activity. Understanding the scope of microRNAs that control this pathway is highly relevant to diseases of perturbed cholesterol metabolism, most notably cardiovascular disease (CVD). Atherosclerosis is a common cause of CVD that involves inflammation and the accumulation of cholesterol-laden cells in the arterial wall. However, several different cell types participate in atherosclerosis, and perturbations in cholesterol homeostasis may have unique effects on the specialized functions of these various cell types. Therefore, our review discusses the current knowledge of microRNA-mediated control of cholesterol homeostasis, followed by speculation as to how these microRNA-mRNA target interactions might have distinctive effects on different cell types that participate in atherosclerosis.

Keywords: atherosclerosis; cholesterol; metabolism; microRNAs.

Figure 1.

Schematic overview of major cholesterol metabolism pathways. After dietary lipid absorption, chylomicrons in the circulation (1) are cleaved by lipoprotein lipase to produce chylomicron remnants (CMRs) (2) and triglycerides, which can be taken up by peripheral tissues (3). CMRs subsequently enter the liver (4) and are repackaged as VLDL particles that are released into the circulation (5). VLDL particles are broken down into IDLs (6) that are further broken down into LDLs by hepatic lipase (7). LDL particles are taken up by peripheral tissues (8a), or cleared by the liver (8b). Efflux of excess cholesterol onto HDL/ApoAI by peripheral tissues occurs via ABCA1/ABCG1 (9). HDL is taken up by the liver (10), and excess cholesterol is then catabolized to bile acids (11) and excreted (12).

Figure 2.

Regulation of VLDL/LDL metabolism by miRNAs. Schematic model of miRNA regulation of VLDL/LDL homeostasis. Regulation of LDL uptake is managed at the level of the LDL receptor as well as its interacting proteins, such as LDLRAP1 and LRP6. Additionally, miRNA regulation of the LDLR-antagonizing proteins IDOL and PCSK9 can serve to regulate LDL uptake in cells by promoting LDLR degradation. Lastly, VLDL biogenesis, which occurs in the liver, can be inhibited by the actions of miR-30c and miR-33 on MTP and NSF, respectively.

Figure 3.

MicroRNA-dependent regulation of cholesterol efflux. Notably, several microRNAs target Abca1, which has an appreciablylong 3′ UTR and effluxes cholesterol to poorly lipidated ApoAI. In addition, miR-34 and miR-33 target Abcg1, which effluxes cholesterol to HDL. Frequently, this regulation of ABC transporter expression influences circulating levels of HDL. In addition to the direct regulation of these transporters, microRNAs, such as miR-613, miR-34, and miR-206, indirectly decrease their expression via repression of LXRα, the major transcriptional driver of ABC transporter expression. Lastly, by targeting mitochondrial SLC25A5, PDK4, and PPARGC1A, miR-33 may impact ATP production and subsequent ABC transporter function.

Figure 4.

Regulation of the cholesterol-sensing SREBP2 pathway by miRNAs. While direct targeting of SREBP2, the master transcriptional regulator of cholesterol biosynthesis, is accomplished by miR-185, several other miRNAs indirectly regulate its activity. For example, miR-26, miR-130b, and miR-96 all target INSIG proteins, which otherwise anchor SREBP2 in the ER membrane in sterol-replete conditions. Additionally, miR-182 targets the ubiquitin ligase FBXW7, which otherwise antagonizes SREBP2 levels.