Identification of liver receptor homolog-1 as a novel regulator of apolipoprotein AI gene transcription.
The orphan nuclear receptor liver receptor homolog-1 (LRH-1) has been reported to play a role in bile acid biosynthesis and reverse cholesterol transport. In this study, we examined the role of LRH-1 in the regulation of the apolipoprotein AI (APOAI) gene. Using RNA interference and adenovirus-mediated overexpression, we show that LRH-1 directly regulates APOAI gene transcription. Transient transfection experiments and EMSAs revealed that LRH-1 directly regulates APOAI transcription by binding to an LRH-1 response element located in the proximal APOAI promoter region. Chromatin immunoprecipitation experiments revealed that LRH-1 binds to the human APO AI promoter in vivo. Finally, we show that the transcriptional repressor SHP (small heterodimer partner) suppressed APOAI gene expression by inhibiting LRH-1 transcriptional activity. Taken together, our results demonstrate that LRH-1 is a novel regulator of APOAI transcription and underscore the role of this receptor in cholesterol homeostasis.
Delerive
Philippe
P
GlaxoSmithKline, Cardiovascular & Urogenital Center of Excellence for Drug Discovery, 91951 Les Ulis, France. pxd14884@gsk.com <pxd14884@gsk.com>
Galardi
Cristin M
CM
Bisi
John E
JE
Nicodeme
Edwige
E
Goodwin
Bryan
B
D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000502:physiology*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000502:physiology; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D014157:Transcription Factors; D014158:Transcription, Genetic
D016632:Apolipoprotein A-I; D017931:DNA Primers; D004268:DNA-Binding Proteins; C082631:NR5A2 protein, human; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors