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