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

Science. 2000 Sep 1;289(5484):1524-9. doi: 10.1126/science.289.5484.1524.

Abstract

Several nuclear hormone receptors involved in lipid metabolism form obligate heterodimers with retinoid X receptors (RXRs) and are activated by RXR agonists such as rexinoids. Animals treated with rexinoids exhibited marked changes in cholesterol balance, including inhibition of cholesterol absorption and repressed bile acid synthesis. Studies with receptor-selective agonists revealed that oxysterol receptors (LXRs) and the bile acid receptor (FXR) are the RXR heterodimeric partners that mediate these effects by regulating expression of the reverse cholesterol transporter, ABC1, and the rate-limiting enzyme of bile acid synthesis, CYP7A1, respectively. Thus, these RXR heterodimers serve as key regulators of cholesterol homeostasis by governing reverse cholesterol transport from peripheral tissues, bile acid synthesis in liver, and cholesterol absorption in intestine.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter 1
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism*
  • Animals
  • Bile Acids and Salts / biosynthesis
  • Biological Transport / drug effects
  • Cholesterol / metabolism*
  • Cholesterol 7-alpha-Hydroxylase / metabolism
  • Cholesterol, Dietary / administration & dosage
  • Cricetinae
  • DNA-Binding Proteins / metabolism
  • Dimerization
  • Gene Expression Regulation / drug effects
  • Glycoproteins / genetics
  • Glycoproteins / metabolism*
  • Homeostasis / drug effects
  • Intestinal Absorption / drug effects*
  • Intestine, Small / metabolism*
  • Ligands
  • Liver / metabolism*
  • Liver X Receptors
  • Macrophages, Peritoneal / metabolism
  • Male
  • Mesocricetus
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Orphan Nuclear Receptors
  • Receptors, Cytoplasmic and Nuclear*
  • Receptors, Retinoic Acid / agonists
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / metabolism*
  • Receptors, Thyroid Hormone / agonists
  • Receptors, Thyroid Hormone / genetics
  • Receptors, Thyroid Hormone / metabolism
  • Retinoid X Receptors
  • Transcription Factors / agonists
  • Transcription Factors / metabolism*

Substances

  • ATP Binding Cassette Transporter 1
  • ATP-Binding Cassette Transporters
  • Bile Acids and Salts
  • Cholesterol, Dietary
  • DNA-Binding Proteins
  • Glycoproteins
  • Ligands
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid
  • Receptors, Thyroid Hormone
  • Retinoid X Receptors
  • Transcription Factors
  • farnesoid X-activated receptor
  • Cholesterol
  • Cholesterol 7-alpha-Hydroxylase