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Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers

J J Repa1, S D Turley, J A Lobaccaro

  • 1Howard Hughes Medical Institute and Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9050, USA.

Science (New York, N.Y.)
|September 1, 2000
PubMed

Insights

RXR heterodimers, activated by rexinoids, regulate cholesterol balance by controlling cholesterol absorption and bile acid synthesis. These nuclear receptors are key to maintaining cholesterol homeostasis.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Lipid Metabolism

Background:

  • Nuclear hormone receptors regulate lipid metabolism.
  • Retinoid X receptors (RXRs) form heterodimers with other receptors.
  • RXR agonists (rexinoids) impact cholesterol balance.

Purpose of the Study:

  • To identify RXR heterodimeric partners involved in lipid metabolism.
  • To elucidate the role of these heterodimers in cholesterol homeostasis.
  • To understand the mechanism of rexinoid action on cholesterol regulation.

Main Methods:

  • Treatment of animals with rexinoids.
  • Analysis of cholesterol balance markers.
  • Studies using receptor-selective agonists for LXRs and FXR.
  • Gene expression analysis of ABC1 and CYP7A1.

Main Results:

  • Rexinoids inhibit cholesterol absorption and repress bile acid synthesis.
  • Oxysterol receptors (LXRs) and bile acid receptor (FXR) are identified as RXR heterodimeric partners.
  • LXR-RXR heterodimers regulate ABC1 expression (reverse cholesterol transport).
  • FXR-RXR heterodimers regulate CYP7A1 expression (bile acid synthesis).

Conclusions:

  • RXR heterodimers are crucial regulators of cholesterol homeostasis.
  • These heterodimers coordinate reverse cholesterol transport, bile acid synthesis, and cholesterol absorption.
  • Targeting RXR heterodimers offers a strategy for managing cholesterol metabolism.

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