Back to Search
Start Over
PPARα Induces the Expression of CAR That Works as a Negative Regulator of PPARα Functions in Mouse Livers.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2023 Feb 16; Vol. 24 (4). Date of Electronic Publication: 2023 Feb 16. - Publication Year :
- 2023
-
Abstract
- The nuclear receptor peroxisome proliferator-activated receptor α (PPARα) is a transcription factor that controls the transcription of genes responsible for fatty acid metabolism. We have recently reported a possible drug-drug interaction mechanism via the interaction of PPARα with the xenobiotic nuclear receptor constitutive androstane receptor (CAR). Drug-activated CAR competes with the transcriptional coactivator against PPARα and prevents PPARα-mediated lipid metabolism. In this study, to elucidate the crosstalk between CAR and PPARα, we focused on the influence of PPARα activation on CAR's gene expression and activation. Male C57BL/6N mice (8-12 weeks old, n = 4) were treated with PPARα and CAR activators (fenofibrate and phenobarbital, respectively), and hepatic mRNA levels were determined using quantitative reverse transcription PCR. Reporter assays using the mouse Car promoter were performed in HepG2 cells to determine the PPARα-dependent induction of CAR. CAR KO mice were treated with fenofibrate, and the hepatic mRNA levels of PPARα target genes were determined. Treatment of mice with a PPARα activator increased Car mRNA levels as well as genes related to fatty acid metabolism. In reporter assays, PPARα induced the promoter activity of the Car gene. Mutation of the putative PPARα-binding motif prevented PPARα-dependent induction of reporter activity. In electrophoresis mobility shift assay, PPARα bound to the DR1 motif of the Car promoter. Since CAR has been reported to attenuate PPARα-dependent transcription, CAR was considered a negative feedback protein for PPARα activation. Treatment with fenofibrate induced the mRNA levels of PPARα target genes in Car -null mice more than those in wild-type mice, suggesting that CAR functions as a negative feedback factor for PPARα.
- Subjects :
- Animals
Male
Mice
Fatty Acids metabolism
Fenofibrate pharmacology
Mice, Inbred C57BL
Receptors, Cytoplasmic and Nuclear metabolism
RNA, Messenger metabolism
Transcription Factors metabolism
Constitutive Androstane Receptor genetics
Constitutive Androstane Receptor metabolism
Liver metabolism
PPAR alpha metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 24
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 36835365
- Full Text :
- https://doi.org/10.3390/ijms24043953