Bile acids reduce SR-BI expression in hepatocytes by a pathway involving FXR/RXR, SHP, and LRH-1.
Hepatic SR-BI mediates uptake of circulating cholesterol into liver hepatocytes where a part of the cholesterol is metabolised to bile acids. In the hepatocytes, bile acids reduce their own synthesis by a negative feedback loop to prevent toxic high levels of bile acids. Bile acid-activated FXR/RXR represses expression of CYP7A1, the rate-limiting enzyme during bile acid synthesis, by inducing the expression of SHP, which inhibits LXR/RXR and LRH-1-transactivation of CYP7A1. The present paper presents data indicating that CDCA suppresses SR-BI expression by the same pathway. As previously reported, LRH-1 induces SR-BI promoter activity. Here we show that CDCA or over-expression of SHP inhibit this transactivation. No FXR-response element was identified in the bile acid-responsive region of the SR-BI promoter (-1200bp/-937bp). However, a binding site for LRH-1 was characterised and shown to specifically bind LRH-1. The present study shows that also the SR-BI-mediated supply of cholesterol, the substrate for bile acid synthesis, is feedback regulated by bile acids.
Malerød
Lene
L
Programme for Cell Biology, Department of Molecular Biosciences, University of Oslo, Norway.
Sporstøl
Marita
M
Juvet
Lene K
LK
Mousavi
Seyed Ali
SA
Gjøen
Tor
T
Berg
Trond
T
Roos
Norbert
N
Eskild
Winnie
W
D000818:Animals; D002478:Cells, Cultured; D002635:Chenodeoxycholic Acid / Q000502:physiology*; D002522:Chlorocebus aethiops; D008076:Cholesterol, HDL / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D047490:Retinoid X Receptor alpha / Q000819:agonists / Q000378:metabolism*; D051122:Scavenger Receptors, Class B / Q000096:biosynthesis*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
D002635:Chenodeoxycholic Acid; D008076:Cholesterol, HDL; D004268:DNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D047490:Retinoid X Receptor alpha; D051122:Scavenger Receptors, Class B; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C082631:NR5A2 protein, human; C495124:SCARB1 protein, human; C099713:nuclear receptor subfamily 0, group B, member 2