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Regulation of Absorption and ABC1-Mediated Efflux of Cholesterol by RXR Heterodimers
J. J. Repa,1S.
D. Turley,2J.-M. A. Lobaccaro,1*J. Medina,3L. Li,3K. Lustig,3B. Shan,3R. A. Heyman,4 J. M. Dietschy,2D. J. Mangelsdorf1
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 treatedwith rexinoids exhibited marked changes in cholesterol balance,including inhibition of cholesterol absorption and repressed bileacid
synthesis. Studies with receptor-selective agonists revealedthat
oxysterol receptors (LXRs) and the bile acid receptor (FXR)are the RXR
heterodimeric partners that mediate these effectsby 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 regulatorsof cholesterol
homeostasis by governing reverse cholesterol transportfrom peripheral
tissues, bile acid synthesis in liver, and cholesterolabsorption in
intestine.
1 Howard Hughes Medical Institute and
Department of Pharmacology,
2 Department of Internal
Medicine, University of Texas Southwestern Medical Center, 5323 Harry
Hines Boulevard, Dallas, TX 75390-9050, USA.
3 Tularik, Two Corporate Drive, South San Francisco,
CA 94080, USA.
4 Ligand Pharmaceuticals, 10255 Science Center Drive, San Diego, CA 92121, USA.
*
Present address: Physiologie Comparée-Endocrinologie
Moléculaire, UMR CNRS 6547-GEEM, Université Blaise Pascal,
63177 AubièreCedex, France.
To whom correspondence should be addressed. E-mail:
davo.mango{at}utsouthwestern.edu
The editors suggest the following Related Resources on Science sites:
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135, 2305-2312
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J. M. Dietschy,