MicroRNAs regulating lipid metabolism in atherogenesis

Abstract

MicroRNAs have emerged as important post-transcriptional regulators of lipid metabolism, and represent a new class of targets for therapeutic intervention. Recently, microRNA-33a and b (miR-33a/b) were discovered as key regulators of metabolic programs including cholesterol and fatty acid homeostasis. These intronic microRNAs are embedded in the sterol response element binding protein genes, SREBF2 and SREBF1, which code for transcription factors that coordinate cholesterol and fatty acid synthesis. By repressing a variety of genes involved in cholesterol export and fatty acid oxidation, including ABCA1, CROT, CPT1, HADHB and PRKAA1, miR-33a/b act in concert with their host genes to boost cellular sterol levels. Recent work in animal models has shown that inhibition of these small non-coding RNAs has potent effects on lipoprotein metabolism, including increasing plasma high-density lipoprotein (HDL) and reducing very low density lipoprotein (VLDL) triglycerides. Furthermore, other microRNAs are being discovered that also target the ABCA1 pathway, including miR-758, suggesting that miRNAs may work cooperatively to regulate this pathway. These exciting findings support the development of microRNA antagonists as potential therapeutics for the treatment of dyslipidaemia, atherosclerosis and related metabolic diseases.

Figure 1. miR-33 simultaneously targets proteins involved in multiple metabolic pathways in the liver

When miR-33a or b is expressed in the liver, there is a decrease in ABCA1, resulting in decreased cholesterol efflux and HDL. miR-33 also decreases fatty acid oxidation and increases VLDL secretion by targeting CROT, Cpt1a, HADHB and AMPKα. Finally, miR-33 inhibits expression of IRS2, resulting in impaired insulin signaling.

Figure 2. Therapeutic actions of anti-miR-33 in the treatment of atherosclerosis

Inhibition of miR-33 in the liver increases the expression of ABCA1, which in turn enhances HDL biogenesis and the reverse cholesterol transport pathway. Anti-sense oligonucleotides targeting miR-33 can also reach plaque macrophages, to increase expression of ABCA1, which promotes cholesterol efflux from these lesional cells. The increase in HDL biogenesis combined with increased cholesterol efflux from macrophages enhances reverse cholesterol transport to the liver for uptake by SR-BI and excretion. These combined effects of anti-miR-33 treatment have been shown to lead to a reduction in atherosclerotic plaque burden. In addition to changes in ABCA1, anti-miR-33 causes derepression of miR-33 target genes involved in fatty acid oxidation and downregulates the expression of genes involved in fatty acid synthesis via repression of SREBP-1. By increasing fatty acid oxidation and decreasing fatty acid synthesis, anti-miR-33 leads to decreased triglyceride production by the liver.

Figure 3. Schematic diagram of the 3′fUTR of ABCA1 showing targeting by miR-33 and mR-758

The sites of miR-33 and miR-758 binding in the 3′UTR of ABCA1 are indicated (S1: site 1, S2: site 2, S3: site 3).