| RRC ID |
45077
|
| Author |
Oda Y, Nakajima M, Tsuneyama K, Takamiya M, Aoki Y, Fukami T, Yokoi T.
|
| Title |
Retinoid X receptor α in human liver is regulated by miR-34a.
|
| Journal |
Biochem Pharmacol
|
| Abstract |
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.
|
| Volume |
90(2)
|
| Pages |
179-87
|
| Published |
2014-7-15
|
| DOI |
10.1016/j.bcp.2014.05.002
|
| PII |
S0006-2952(14)00263-9
|
| PMID |
24832862
|
| MeSH |
3' Untranslated Regions
Aged
Aged, 80 and over
Cytochrome P-450 CYP3A / genetics
Cytochrome P-450 CYP3A / metabolism
Cytochrome P-450 Enzyme System / genetics
Cytochrome P-450 Enzyme System / metabolism
Female
Gene Expression Regulation*
Genes, Reporter
HEK293 Cells
Hep G2 Cells
Humans
Liver Cirrhosis / genetics
Liver Cirrhosis / metabolism*
Liver Cirrhosis / pathology
Luciferases / genetics
Luciferases / metabolism
Male
MicroRNAs / genetics
MicroRNAs / metabolism*
Middle Aged
Open Reading Frames
RNA Cleavage
RNA Stability
Retinoic Acid 4-Hydroxylase
Retinoid X Receptor alpha / genetics
Retinoid X Receptor alpha / metabolism*
Signal Transduction
Transcription, Genetic
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism
|
| IF |
4.96
|
| Times Cited |
28
|
|
WOS Category
|
PHARMACOLOGY & PHARMACY
|
| Resource |
| Human and Animal Cells |
Hep G2
HuH-7 |
