Hypolipidemic effect of oleanolic acid is mediated by the miR-98-5p/PGC-1β axis in high-fat diet-induced hyperlipidemic mice

Oleanolic acid (OA) is an active component of the traditional Chinese herb Olea europaea L. and has been found to exhibit a significant lipid-lowering effect; however, its direct molecular target is still unknown, which limits its clinical application and the possible structure modification to improve its beneficial functions. In this regard, we carried out the present study to identify potential hepatic targets of OA to mediate its lipid-lowering effect. We found that both acute and chronic OA treatments reduced serum levels of triglycerides, total cholesterol, and LDL cholesterol, and decreased hepatic expression levels of peroxisome proliferator-activated receptor- gamma coactivator-1 beta (PGC-1 beta), which is an important regulator in maintaining hepatic lipid homeostasis, and its down stream target genes. Of note, liver-specific knockdown of PGC-1 beta recapitulated the hypolipidemic effects of OA. At the molecular level, OA accelerated mRNA degradation of PGC-1 beta. Microarray analysis revealed a host of microRNAs that potentially mediate OA-induced PGC-1 beta mRNA degradation, among which, miR-98-5p significantly inhibited activity of Pgc-1 beta 3 ' UTR as well as PGC-1 beta expression and promoted its mRNA degradation. Conversely, miR-98-5p inhibitors blunted the inhibitory effects of OA on PGC-1 beta expression. Collectively, our data demonstrated that OA ameliorated hyperlipidemia, likely via regulation of the miR-98-5p/ PGC-1 beta axis.