MicroRNA modulation of cholesterol homeostasis

Abstract

Although the roles of the sterol response element binding protein-1 (SREBP1) and SREBP2 transcription factors in regulating fatty acid and cholesterol synthesis and uptake have been known for some time, it was recently discovered that 2 related microRNAs (miRs), miR-33a and miR-33b, are embedded in these genes. Studies indicate that miR-33a and miR-33b act with their host genes, Srebp2 and Srebp1, respectively, to reciprocally regulate cholesterol homeostasis and fatty acid metabolism in a negative feedback loop. miR-33 has been shown to posttranscriptionally repress key genes involved in cellular cholesterol export and high-density lipoprotein metabolism (Abca1, Abcg1, Npc1), fatty acid oxidation (Crot, Cpt1a, Hadhb, Ampk), and glucose metabolism (Sirt6, Irs2). Delivery of inhibitors of miR-33 in vitro and in vivo relieves repression of these genes, resulting in upregulation of the associated metabolic pathways. In mouse models, miR-33 antagonism has proven to be an effective strategy for increasing plasma high-density lipoprotein cholesterol and fatty acid oxidation and protecting from atherosclerosis. These exciting findings have opened up promising new avenues for the development of therapeutics to treat dyslipidemia and other metabolic disorders.

Figure 1

Evolutionary conserved sequences in the 3′UTR of ABCA1 is partially complementary to miR-33. Annealing of miR-33 to some sequences are shown

Figure 2

Pathways by which activated miR-33 may contribute to regulating cholesterol, fatty acid and glucose metabolism, cell proliferation and transcription. Transcriptional activation of SREBP-2 under low intracellular cholesterol levels and SREBP-1 upon insulin-LXR stimulation leads the co-transcription of miR-33a and miR-33b respectively. miR-33a/b target several genes involved in the regulation of cholesterol efflux and trafficking, fatty acid oxidation, cell proliferation and cell cycle progression, and glucose metabolism.