The role of the nuclear receptor CAR as a coordinate regulator of hepatic gene expression in defense against chemical toxicity

Arch Biochem Biophys. 2003 Jan 1;409(1):207-11. doi: 10.1016/s0003-9861(02)00456-3.

Abstract

The nuclear receptor CAR (constitutive active receptor) mediates the induction of transcription of cytochrome P450 (CYP) genes by phenobarbital (PB) and PB-type inducers. A recent study using CAR-null mice has shown that CAR regulates not only the CYP genes but also other genes encoding various drug/steroid-metabolizing enzymes. In addition to coordinating these enzymes, CAR plays other roles in hepatic gene expression: CAR represses various genes including carnitine palmitoyltransferase 1a and phosphoenolpyruvate carboxykinase 1 in response to PB, and the receptor regulates the constitutive expression of genes such as squalene epoxidase. On the other hand, induction of certain genes such as amino levulinate synthase 1 by PB is not regulated by CAR. Here we describe diverse roles of CAR in hepatic gene expression with a particular focus on endogenous substances such as cholesterol, bilirubin, and steroid hormones.

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives*
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
  • 5-Aminolevulinate Synthetase / metabolism
  • Animals
  • Blotting, Northern
  • Calcium / metabolism
  • Carnitine O-Palmitoyltransferase / metabolism
  • Cells, Cultured
  • Cholesterol / metabolism
  • Cytoplasm / metabolism
  • Dose-Response Relationship, Drug
  • Estrogens / pharmacology
  • Gene Expression Regulation*
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Transgenic
  • Models, Biological
  • Oligonucleotide Array Sequence Analysis
  • Oxygenases / metabolism
  • Phosphoenolpyruvate Carboxykinase (ATP) / metabolism
  • Protein Structure, Tertiary
  • RNA, Messenger / metabolism
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Squalene Monooxygenase
  • Transcription Factors / metabolism*
  • Transcription Factors / physiology*
  • Transcription, Genetic
  • Two-Hybrid System Techniques

Substances

  • Estrogens
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • constitutive androstane receptor
  • KN 62
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • Cholesterol
  • Oxygenases
  • Squalene Monooxygenase
  • Carnitine O-Palmitoyltransferase
  • 5-Aminolevulinate Synthetase
  • Phosphoenolpyruvate Carboxykinase (ATP)
  • Calcium