MicroRNA-30c Reduces Hyperlipidemia and Atherosclerosis by Decreasing Lipid Synthesis and Lipoprotein Secretion.

Abstract

Excess lipids in plasma are a risk factor for cardiovascular and metabolic disorders. Our studies show that microRNA-30c (miR-30c) targets the 3 untranslated region (3 UTR) of MTP mRNA and induces degradation. This leads to reductions in the secretion of apolipoprotein B (apoB). In Western diet fed mice, miR-30c reduces hyperlipidemia and atherosclerosis by decreasing both the production of apoB-containing lipoproteins and lipid biosynthesis. The coordinate reductions are achieved without increasing hepatic lipids or increases in plasma transaminases. These studies suggest that miR-30c targets MTP, reduces apoB secretion, lowers plasma lipids, and prevents atherosclerosis. In addition, we hypothesized that miR-30c might target MTP mRNA more efficiently if the seed and supplementary sequences were studied further. Since miR-30c targets MTP mRNA by binding to 3 UTR via its seed and supplementary sequence, we designed various mutations in the miR-30c binding site of MTP. The studies reveal the importance of the binding of the supplementary sequence in miR-30c with sequences in the 3 UTR of MTP. Furthermore, we also examined the role of miR-30c target genes involved in lipid synthesis. These studies have shed light on how miR-30c lowers plasma lipids without causing steatosis. The studies herein suggest that miR-30c targets both apoBlipoprotein production and lipid synthesis; they work together as anti-hyperlipidemic and atheroprotective. Elucidation of improved binding to MTP mRNA and another lipid metabolism pathway targeted by miR-30c may help develop new therapeutic options. Development of a treatment modality using miR-30c may be beneficial in lowering plasma lipids.