Original Research ARTICLE
Transcriptional Repression of CYP3A4 by Increased miR-200a-3p and miR-150-5p Promotes Steatosis in vitro
- 1Center of Clinical Pharmacology, Third Xiangya Hospital, Central South University, China
- 2Department of Pharmacy, Third Xiangya Hospital, Central South University, China
- 3Institute of Clinical Pharmacology, Central South University, China
- 4Center for Medical Genetics, Central South University, China
Hepatic cytochrome P450 enzyme activities correlate with non-alcoholic fatty liver disease (NAFLD) and hepatic steatosis. The decreased activity of CYP3A4, an important drug-metabolizing enzyme, is associated with the progression of NAFLD. CYP3A4 is predicted as a target gene of miR-200a-3p and miR-150-5p by MicroInspector and TargetScan algorithms analysis. Here, we found decreased CYP3A4 and increased miR-200a-3p and miR-150-5p in LO2 cells with free fatty acid (FFA)-induced steatosis. Dual-luciferase assay confirmed that both miR-200a-3p and miR-150-5p targeted 3′-untranslated region (3’-UTR) of CYP3A4, and that such interaction was abolished by miRNA binding site mutations in 3’-UTR of CYP3A4. Using miR-200a-3p and miR-150-5p mimics and inhibitors, we further confirmed that endogenous CYP3A4 was regulated post-transcriptionally by miR-200a-3p or miR-150-5p. Moreover, miR-200a-3p and miR-150-5p inhibitors attenuated FFA-induced steatosis in LO2 cells and such effect was dependent on CYP3Y4 expression. These results suggest that miR-200a-3p and miR-150-5p, through directly targeting 3′-UTR of CYP3A4, contribute to the development of FFA-induced steatosis.
Keywords: NAFLD, CYP3A4, MiR-200a-3p, miR-150-5p, LO2 cell line
Received: 03 Oct 2018;
Accepted: 06 May 2019.
Edited by:Yujing Li, Emory University, United States
Reviewed by:Jun-An Chen, Institute of Statistical Science, Academia Sinica, Taiwan
Mahshid Malakootian, Rajaei Cardiovascular, Medical and Research center, Iran University of Medical Sciences, Iran
Copyright: © 2019 Wang, Liu, Peng, Guo, Chen, Huang, TAN, Huang and Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Prof. Zhijun Huang, Center of Clinical Pharmacology, Third Xiangya Hospital, Central South University, Changsha, China, email@example.com
Prof. Guoping Yang, Center of Clinical Pharmacology, Third Xiangya Hospital, Central South University, Changsha, China, firstname.lastname@example.org