A key role for orphan nuclear receptor liver receptor homologue-1 in activation of fatty acid synthase promoter by liver X receptor.
Liver X receptor (LXR) activates fatty acid synthase (FAS) gene expression through binding to a DR-4 element in the promoter. We show that a distinct nuclear receptor half-site 21 bases downstream of the DR-4 element is also critical for the response of FAS to LXR but is not involved in LXR binding to DNA. This half-site specifically binds liver receptor homologue-1 (LRH-1) in vitro and in vivo, and we show LRH-1 is required for maximal LXR responsiveness of the endogenous FAS gene as well as from promoter reporter constructs. We also demonstrate that LRH-1 stimulation of the FAS LXR response is blocked by the addition of small heterodimer partner (SHP) and that FAS mRNA is overexpressed in SHP knock-out animals, providing evidence that FAS is an in vivo target of SHP repression. Taken together, these findings identify the first direct lipogenic gene target of LRH-1/SHP repression and provide a mechanistic explanation for bile acid repression of FAS and lipogenesis recently reported by others.
Matsukuma
Karen E
KE
Department of Molecular Biology and Biochemistry, School of Biological Sciences and Center for Diabetes Research and Treatment, University of California, Irvine, CA 92697-3900, USA.
Wang
Li
L
Bennett
Mary K
MK
Osborne
Timothy F
TF
D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D064429:Fatty Acid Synthases / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology*; D000071518:Liver X Receptors; D051379:Mice; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C082631:NR5A2 protein, human; C431936:Nr5a2 protein, mouse; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C099713:nuclear receptor subfamily 0, group B, member 2; D064429:Fatty Acid Synthases