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FASEB J. 2017 Mar;31(3):1085-1096. doi: 10.1096/fj.201601022R. Epub 2016 Nov 30.

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

Chen S1,2, Wen X1, Zhang W3, Wang C3, Liu J4, Liu C5,3,6.

Author information

1
Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China; and.
2
Jiangsu Key Laboratory of Human Functional Genomics, Nanjing Medical University, Nanjing, Jiangsu, China.
3
School of Life Sciences, China Pharmaceutical University, Nanjing, China; and.
4
Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China; and junincpu@yahoo.com.
5
Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China; and changliu@njnu.edu.cn.
6
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.

Abstract

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-γ coactivator-1β (PGC-1β), which is an important regulator in maintaining hepatic lipid homeostasis, and its downstream target genes. Of note, liver-specific knockdown of PGC-1β recapitulated the hypolipidemic effects of OA. At the molecular level, OA accelerated mRNA degradation of PGC-1β. Microarray analysis revealed a host of microRNAs that potentially mediate OA-induced PGC-1β mRNA degradation, among which, miR-98-5p significantly inhibited activity of Pgc-1β 3' UTR as well as PGC-1β expression and promoted its mRNA degradation. Conversely, miR-98-5p inhibitors blunted the inhibitory effects of OA on PGC-1β expression. Collectively, our data demonstrated that OA ameliorated hyperlipidemia, likely via regulation of the miR-98-5p/PGC-1β axis.-Chen, S., Wen, X., Zhang, W., Wang, C., Liu, J., Liu, C. Hypolipidemic effect of oleanolic acid is mediated by the miR-98-5p/PGC-1β axis in high-fat diet-induced hyperlipidemic mice.

KEYWORDS:

lipid-lowering function; liver; miRNA; molecular target; triterpenoid compound

PMID:
27903618
DOI:
10.1096/fj.201601022R
[Indexed for MEDLINE]

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