Regulation of anti-atherogenic apolipoprotein M gene expression by the orphan nuclear receptor LRH-1.
The orphan nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) has been reported to play a crucial role in early development, in the control of the hepatic inflammatory response, in intestinal cell crypt renewal as well as in bile acid biosynthesis and reverse cholesterol transport (RCT). Here, we report the identification of apolipoprotein M (APOM) as a novel target gene for LRH-1. Using gene-silencing experiments, adenovirus-mediated overexpression, transient transfection, and chromatin immunoprecipitation (ChIP) assays, it is shown that LRH-1 directly regulates human and mouse APOM transcription by binding to an LRH-1 response element located in the proximal APOM promoter region. In addition, we demonstrate that bile acids suppress APOM expression in a SHP-dependent manner in vitro and in vivo by inhibiting LRH-1 transcriptional activity on the APOM promoter as demonstrated by in vivo ChIP assay. Taken together, our results demonstrate that LRH-1 is a novel regulator of APOM transcription and further extend the role of this orphan nuclear receptor in lipoprotein metabolism and cholesterol homeostasis.
Venteclef
Nicolas
N
Cardiovascular and Urogenital Center of Excellence for Drug Discovery, GlaxoSmithKline, 25 Avenue du Quebec, 91951 Les Ulis, France.
Haroniti
Anna
A
Tousaint
Jean-Jacques
JJ
Talianidis
Iannis
I
Delerive
Philippe
P
D000818:Animals; D001053:Apolipoproteins / Q000235:genetics*; D000075243:Apolipoproteins M; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D054834:Lipocalins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
C400523:APOM protein, human; D001053:Apolipoproteins; D000075243:Apolipoproteins M; D017931:DNA Primers; D004268:DNA-Binding Proteins; D054834:Lipocalins; C082631:NR5A2 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors