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PMID: 10968783 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

Science (New York, N.Y.) ·Vol. 289 ·No. 5484 ·2000-09-01 ·Pages 1524-9

Repa JJ, Turley SD, Lobaccaro JA, Medina J, Li L, Lustig K, Shan B, Heyman RA, Dietschy JM, Mangelsdorf DJ

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.

MeSH Terms
ATP Binding Cassette Transporter 1 ATP-Binding Cassette Transporters/genetics,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,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,genetics,metabolism Receptors, Thyroid Hormone/agonists,genetics,metabolism Retinoid X Receptors Transcription Factors/agonists,metabolism
Chemicals
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
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Repa J J
Howard Hughes Medical Institute and Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9050, USA.
Turley S D
Lobaccaro J A
Medina J
Li L
Lustig K
Shan B
Heyman R A
Dietschy J M
Mangelsdorf D J
Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
0036-8075
Published
2000-09-01
Pages
1524-9
Language
English
Region
United States
NLM ID
0404511
Subset
IM
Grants
NHLBI NIH HHS · R37 HL 09610 · United States
Corrections
CommentIn
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