Biochemical and Biophysical Research Communications
Bile acids reduce SR-BI expression in hepatocytes by a pathway involving FXR/RXR, SHP, and LRH-1☆
Section snippets
Materials and methods
Plasmids. Expression plasmids for human RXRα (RXRα-pCMV), SHP-pSG5, and β-galactosidase-pSV were kindly provided by Dr. Hilde Nebb (Institute of Nutrition Research, University of Oslo). Human LRH-1-pSG5 and FXR-pCMX were from Dr. Bryan Goodwin (Nuclear Receptor Sysmtem Research, GlaxoSmithKline Research & Development, USA) and Dr. Heidi R. Kast (Department of Biological Chemistry and Medicine, University of California, Los Angeles, USA) [43], respectively. A luciferase reporter construct
Bile acids decrease hepatic SR-BI protein expression
Rats were fed standard chow (control animals) or 1% (w/w) TCA or 2% (w/w) cholestyramine supplemented diets for 6 days. The hepatic SR-BI expression (protein and mRNA) was measured using Western blotting (Fig. 1A) and quantitative real time RT-PCR (Fig. 1B). A significant reduction in both SR-BI protein and mRNA levels was observed in rats treated with 1% (w/w) TCA compared to control fed rats. On the other hand, hepatic SR-BI expression was induced in response to 2% (w/w) cholestyramine
Discussion
Transcription of SR-BI in hepatocytes was found to be inhibited by bile acids both in vivo and in vitro. The negative regulation is most likely mediated by FXR/RXR since the same effect was obtained using the specific, synthetic FXR-agonist GW404764. Furthermore, we interpret this effect to be indirect since no response element for FXR/RXR was found in the bile acid-responsive region of the SR-BI promoter. We conclude that hepatocytic SR-BI is a novel FXR-target gene although this issue is
Acknowledgments
We thank Drs. Hilde Nebb, Bryan Goodwin, Helen H. Hobbs, and Heidi R. Kast for providing us with the necessary expression plasmids. A special thank to German Tapia and Folkert Kuipers for valuable help with the in vivo experiments. The National Research Council and Norwegian Cancer Society funded this work.
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Abbreviations: CDCA, chenodeoxycholic acid; CETP, cholesteryl ester transfer protein; CYP7A1, cholesterol 7α-hydroxylase; CYP27, sterol 27-hydroxylase; FXR, farnesoid X receptor; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; LRH-1, liver receptor homologue-1; LXR, liver X receptor; RXR, 9-cis-retinoic acid receptor; SHP, small heterodimer partner; SR-BI, scavenger receptor class B, type I; TCA, taurocholate.
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These authors contributed equally to the present work.