Retinoid X receptor α in human liver is regulated by miR-34a.
Retinoid X receptor α (RXRα) forms a heterodimer with numerous nuclear receptors to regulate drug- or lipid-metabolizing enzymes. In this study, we investigated whether human RXRα is regulated by microRNAs. Two potential recognition elements of miR-34a were identified in the RXRα mRNA: one in the coding region and the other in the 3'-untranslated region (3'-UTR). Luciferase assays revealed that miR-34a recognizes the element in the coding region. The overexpression of miR-34a in HepG2 cells significantly decreased the endogenous RXRα protein and mRNA levels. The stability of RXRα mRNA was decreased by the overexpression of miR-34a, indicating that miR-34a negatively regulates RXRα expression by facilitating mRNA degradation. We found that the miR-34a-dependent down-regulation of RXRα decreases the induction of CYP26 and the transactivity of CYP3A4. miR-34a has been reported to be up-regulated by p53, which has an ability to promote liver fibrosis. The p53 activation resulted in an increase of the miR-34a level and a decrease of the RXRα protein level. In addition, the miR-34a levels in eight fibrotic livers were higher than those in six normal livers, and the reverse trend was found for the RXRα protein levels. An inverse correlation was observed between the miR-34a and the RXRα protein levels in the 14 samples. Taken together, the data show that miR-34a negatively regulates RXRα expression in human liver, and affects the expression of its downstream genes. This miR-34a-dependent regulation might be the underlying mechanism responsible for the decreased expression of the RXRα protein in fibrotic livers.
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Yuki
Y
Oda
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. Electronic address: nmiki@p.kanazawa-u.ac.jp.
Miki
M
Nakajima
Graduate School of Medicine and Pharmaceutical Science, University of Toyama, Sugitani, Toyama 930-0194, Japan.
Koichi
K
Tsuneyama
Department of Legal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka 020-8505, Japan.
Masataka
M
Takamiya
Department of Legal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka 020-8505, Japan.
Yasuhiro
Y
Aoki
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Tatsuki
T
Fukami
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Tsuyoshi
T
Yokoi
D020413:3' Untranslated Regions; D000368:Aged; D000369:Aged, 80 and over; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D016366:Open Reading Frames; D059367:RNA Cleavage; D020871:RNA Stability; D000072516:Retinoic Acid 4-Hydroxylase; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D020413:3' Untranslated Regions; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D047490:Retinoid X Receptor alpha; D016159:Tumor Suppressor Protein p53; D003577:Cytochrome P-450 Enzyme System; D008156:Luciferases; D051544:Cytochrome P-450 CYP3A; D000072516:Retinoic Acid 4-Hydroxylase; C510163:CYP3A4 protein, human
9-Cis-retinoic acid (PubChem CID: 449171); All-trans-retinoic acid (PubChem CID: 444795); Etoposide (PubChem CID: 36462); Fibrosis; Post-transcriptional regulation; RXRα; Rifampicin (PubChem CID: 5381226); microRNA; p53