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Constitutive androstane/active receptor is a target of retinoic acid receptor in humans

Kosuke Saito1, Kaoru Kobayashi, Yuki Mizuno

  • 1Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.

Biochemical Pharmacology
|March 10, 2010
PubMed

Insights

Retinoic acid receptor alpha (RAR alpha) activates the human CAR gene by binding to a specific DNA region. This finding sheds light on the regulation of drug-metabolizing enzymes and hepatic functions.

Area of Science:

  • Molecular Biology
  • Hepatology
  • Pharmacology

Background:

  • Constitutive androstane/active receptor (CAR) is a key transcription factor for drug metabolism and hepatic gluconeogenesis.
  • Regulation of the CAR gene itself is not well understood.
  • Retinoic acid receptor alpha (RAR alpha) is a nuclear receptor involved in various cellular processes.

Purpose of the Study:

  • To investigate the role of RAR alpha in the transcriptional regulation of the human CAR gene.
  • To identify the specific region and mechanism by which RAR alpha interacts with the CAR gene.

Main Methods:

  • Treatment of human primary hepatocytes and HepG2 cells with all-trans retinoic acid.
  • Analysis of human CAR promoter activity using reporter assays.
  • Site-directed mutagenesis of the identified CAR regulatory element (cRARE).
  • Gel mobility shift and chromatin immunoprecipitation assays to confirm protein-DNA binding.

Main Results:

  • All-trans retinoic acid increased CAR mRNA expression in human cells.
  • RAR alpha co-expression enhanced human CAR promoter activity.
  • Mutation of the cRARE region abolished RAR alpha-mediated activation.
  • RAR alpha was demonstrated to directly bind to the cRARE in the CAR gene intron.

Conclusions:

  • RAR alpha transactivates the human CAR gene by binding to the cRARE within intron 1.
  • The rat CAR gene lacks the cRARE, explaining its lack of activation by all-trans retinoic acid.
  • RAR alpha-mediated up-regulation of CAR in the human liver may influence retinoid metabolism, though physiological significance requires further study.

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