Abstract 16635: miR-33 as a Therapeutic Target for the Metabolic Syndrome
Many diseases result from perturbations in cholesterol and fatty acid homeostasis including atherosclerosis, type II diabetes, and metabolic syndrome. Recent advances from our group and others have shown that miR-33, an intronic microRNA (miRNA) located within the sterol response element-binding protein (SREBP)-2 and -1 genes, regulates lipid homeostasis in concert with its host genes. In addition to suppressing the expression of the cholesterol transporter, ABCA1, miR-33 also targets key enzymes involved in the regulation of fatty acid oxidation including CROT, CPT1a, HADHB, and AMPKα. In addition, miR-33 also targets the insulin receptor substrate 2 (IRS-2), an essential component of the insulin signaling pathway. To uncover the role of miR-33 in lipid metabolism in vivo, we assessed the impact of miR-33 inhibition in mice fed a chow and high fat diet (HFD). Following a five-month treatment with 2’-O-methoxyethyl (2’MOE) phosphorothioate ASO (miR-33 ASO) or control anti-sense oligonucleotides (control ASO), plasma lipid concentrations, VLDL-secretion, and glucose/insulin levels were determined. Notably, anti-miR-33 treated mice showed a significant increase in HDL cholesterol levels compared to controls. These data demonstrate the efficacy of raising HDL levels by miR-33 inhibitors and support targeting of miR-33 as a therapeutic strategy to regulate pathways controlling three of the risk factors of metabolic syndrome, specifically, levels of HDL, triglycerides, and insulin signaling.
- © 2011 by American Heart Association, Inc.