Liver X receptor alpha is a transcriptional repressor of the uncoupling protein 1 gene and the brown fat phenotype.
The adipocyte integrates crucial information about metabolic needs in order to balance energy intake, storage, and expenditure. Whereas white adipose tissue stores energy, brown adipose tissue is a major site of energy dissipation through adaptive thermogenesis mediated by uncoupling protein 1 (UCP1) in mammals. In both white and brown adipose tissue, nuclear receptors and their coregulators, such as peroxisome proliferator-activated receptor gamma (PPARgamma) and PPARgamma coactivator 1alpha (PGC-1alpha), play key roles in regulating their development and metabolic functions. Here we show the unexpected role of liver X receptor alpha (LXRalpha) as a direct transcriptional inhibitor of beta-adrenergic receptor-mediated, cyclic AMP-dependent Ucp1 gene expression through its binding to the critical enhancer region of the Ucp1 promoter. The mechanism of inhibition involves the differential recruitment of the corepressor RIP140 to an LXRalpha binding site that overlaps with the PPARgamma/PGC-1alpha response element, resulting in the dismissal of PPARgamma. The ability of LXRalpha to dampen energy expenditure in this way provides another mechanism for maintaining a balance between energy storage and utilization.
Wang
Haibo
H
The Hamner Institutes for Health Sciences, 6 Davis Drive, P.O. Box 12137, Research Triangle Park, NC 27709, USA.
Zhang
Yuan
Y
Yehuda-Shnaidman
Einav
E
Medvedev
Alexander V
AV
Kumar
Naresh
N
Daniel
Kiefer W
KW
Robidoux
Jacques
J
Czech
Michael P
MP
Mangelsdorf
David J
DJ
Collins
Sheila
S
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D052437:Adipocytes, Brown / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured / Q000166:cytology / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D007473:Ion Channels / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D000078723:Nuclear Receptor Interacting Protein 1; D057093:Orphan Nuclear Receptors; D010101:Oxygen Consumption; D047495:PPAR gamma / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D000071256:Uncoupling Protein 1
D048868:Adaptor Proteins, Signal Transducing; D000318:Adrenergic beta-Agonists; D004268:DNA-Binding Proteins; D007473:Ion Channels; D000071518:Liver X Receptors; D024101:Mitochondrial Proteins; C000605214:Nr1h3 protein, mouse; D009687:Nuclear Proteins; D000078723:Nuclear Receptor Interacting Protein 1; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D005576:Colforsin