A Regulatory Role for MicroRNA 33(star) in Controlling Lipid Metabolism Gene Expression

作者：Goedeke Leigh; Vales Lara Frances M; Fenstermaker Michael; Cirera Salinas Daniel; Chamorro Jorganes Aranzazu; Ramirez Cristina M; Mattison Julie A; de Cabo Rafael; Suarez Yajaira; Fernandez Hernando Carlos^*

来源：Molecular and Cellular Biology, 2013, 33(11): 2339-2352.

DOI：10.1128/MCB.01714-12

hsa-miR-33a and hsa-miR-33b, intronic microRNAs (miRNAs) located within the sterol regulatory element-binding protein 2 and 1 genes (Srebp-2 and -1), respectively, have recently been shown to regulate lipid homeostasis in concert with their host genes. Although the functional role of miR-33a and -b has been highly investigated, the role of their passenger strands, miR-33a(star) and -b(star), remains unclear. Here, we demonstrate that miR-33a(star) and -b(star) accumulate to steady-state levels in human, mouse, and nonhuman primate tissues and share a similar lipid metabolism target gene network as their sister strands. Analogous to miR33, miR-33(star) represses key enzymes involved in cholesterol efflux (ABCA1 and NPC1), fatty acid metabolism (CROT and CPT1a), and insulin signaling (IRS2). Moreover, miR-33(star) also targets key transcriptional regulators of lipid metabolism, including SRC1, SRC3, NFYC, and RIP140. Importantly, inhibition of either miR-33 or miR-33(star) rescues target gene expression in cells overexpressing pre-miR-33. Consistent with this, overexpression of miR-33(star) reduces fatty acid oxidation in human hepatic cells. Altogether, these data support a regulatory role for the miRNA(star) species and suggest that miR-33 regulates lipid metabolism through both arms of the miR-33/miR-33(star) duplex.

• 出版日期2013-6