Journal
FRONTIERS IN GENETICS
Volume 10, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fgene.2019.00484
Keywords
non-alcoholic fatty liver disease; CYP3A4; miR 200a 3p; miR-150-5p; LO2 cell line
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Funding
- National Scientific Foundation of China [81673520, 81673519]
- New Xiangya Talent Project of the Third Xiangya Hospital of Central South University [20180302]
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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.
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