Binding of Drug-Activated CAR/Nr1i3 Alters Metabolic Regulation in the Liver

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Updated: Sep 22, 2026

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
10:51

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists

Published on: November 15, 2013

Jianmin Tian1, Rebecca Marino1, Carla Johnson1

  • 1Department of Pathology, School of Medicine, University of Pittsburgh, 200 Lothrop St, Pittsburgh, PA 15261, USA.

Iscience
|November 6, 2018
PubMed

Insights

The constitutive androstane receptor (CAR) controls liver detoxification and metabolism. CAR activation alters gene expression, impacting metabolic pathways and liver growth by competing with other nuclear receptors.

Area of Science:

  • Hepatology
  • Molecular Biology
  • Pharmacology

Background:

  • The constitutive androstane receptor (CAR) is a key regulator of hepatic drug and xenobiotic detoxification.
  • CAR activation by ligands triggers nuclear translocation and stimulates detoxification gene expression, but also influences metabolism and liver growth.

Purpose of the Study:

  • To elucidate the genome-wide early binding patterns of CAR and its partner RXRα.
  • To investigate the impact of CAR binding on H4K5 acetylation.
  • To understand how CAR influences the regulation of metabolic and detoxification genes.

Main Methods:

  • Genome-wide analysis of CAR and RXRα binding.
  • Assessment of H4K5 acetylation.
  • Analysis of gene expression changes in response to CAR activation.

Main Results:

  • CAR regulates a broad spectrum of genes involved in lipid, carbohydrate, and energy metabolism, in addition to detoxification.
  • CAR activation leads to increased H4K5 acetylation upon gene stimulation, but not upon inhibition.
  • Transcriptional inhibition occurs when CAR co-binds with HNF4α, PPARα, or FXR on enhancers, indicating functional competition.

Conclusions:

  • CAR's role extends beyond detoxification to the intricate regulation of metabolic pathways.
  • Competition between CAR and other nuclear receptors (HNF4α, PPARα, FXR) at enhancers is crucial for coordinating metabolic shifts.
  • Drug-activated CAR acts as a novel competitor, constitutively disrupting the normal balance of metabolic gene regulation.
Keywords:
GenomicsMolecular Mechanism of Gene RegulationTranscriptomics

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