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Hepatic expression of thyroid hormone-responsive spot 14 protein is regulated by constitutive androstane receptor

Cyril Breuker1, Amélie Moreau, Laila Lakhal

  • 1Institut National de la Santé et de la Recherche Médicale, Unité 632, 1919 Route de Mende, F-34293 Montpellier, France.

Endocrinology
|February 27, 2010
PubMed

Insights

Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) activators increase lipogenic gene THRSP expression. This may promote fatty liver disease and insulin resistance.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Hepatology

Background:

  • Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are nuclear receptors primarily known for xenobiotic metabolism.
  • Emerging evidence suggests these receptors also influence hepatic lipid metabolism.

Purpose of the Study:

  • To investigate the role of CAR and PXR in regulating the lipogenic gene thyroid hormone-responsive spot 14 protein (THRSP).
  • To determine if CAR and PXR directly activate THRSP gene expression.

Main Methods:

  • Treatment of human hepatocytes and wild-type/CAR null mice with CAR activators.
  • Analysis of THRSP gene expression.
  • Reporter assays to assess promoter transactivation.
  • Gel-shift analysis to study receptor-DNA binding.

Main Results:

  • CAR activators significantly increased THRSP expression in human hepatocytes and wild-type mice, but not in CAR null mice.
  • CAR directly transactivates the THRSP promoter via a specific response element.
  • CAR/retinoid X receptor complex binds to the identified response element on the THRSP promoter.

Conclusions:

  • The THRSP gene is a direct target of CAR and PXR.
  • Activation of CAR/PXR may lead to increased hepatic de novo lipogenesis.
  • This process could contribute to the development of fatty liver disease and insulin resistance.

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