Bile acids reduce SR-BI expression in hepatocytes by a pathway involving FXR/RXR, SHP, and LRH-1

• Published in: Biochemical and biophysical research communications Vol. 336; no. 4; pp. 1096 - 1105
• Main Authors: Malerød, Lene, Sporstøl, Marita, Juvet, Lene K., Mousavi, Seyed Ali, Gjøen, Tor, Berg, Trond, Roos, Norbert, Eskild, Winnie
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.11.2005
• Subjects: Animals; Bile acids; Cells, Cultured; Cercopithecus aethiops; Chenodeoxycholic Acid - physiology; Cholesterol, HDL - metabolism; DNA-Binding Proteins - metabolism; FXR; Gene Expression Regulation; Genes, Reporter; Hepatocytes - metabolism; Humans; Liver; LRH-1; Male; Mice; Promoter Regions, Genetic; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear - metabolism; Retinoid X Receptor alpha - agonists; Retinoid X Receptor alpha - metabolism; Scavenger Receptors, Class B - biosynthesis; SHP; Signal Transduction; SR-BI; Transcription Factors - metabolism; FXR; SR-BI; SHP; Bile acids; LRH-1; Liver
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2005.08.237

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 (−1200 bp/−937 bp). 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.