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Front Genet. 2019 May 28;10:484. doi: 10.3389/fgene.2019.00484. eCollection 2019.

Transcriptional Repression of CYP3A4 by Increased miR-200a-3p and miR-150-5p Promotes Steatosis in vitro.

Huang Z1,2, Wang M1,3, Liu L1, Peng J1,2, Guo C1, Chen X4, Huang L1,2, Tan J5, Yang G1,2.

Author information

1
Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, China.
2
Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, China.
3
Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China.
4
Institute of Clinical Pharmacology, Central South University, Changsha, China.
5
Center for Medical Genetics, Life Science School, Central South University, Changsha, China.

Abstract

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 analyses. 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 the 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 posttranscriptionally 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:

CYP3A4; LO2 cell line; miR-150-5p; miR-200a-3p; non-alcoholic fatty liver disease

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