QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.105.097758v1 317/1/317    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Deng, R. Articles by Yan, B. Search for Related Content PubMed PubMed Citation Articles by Deng, R. Articles by Yan, B.

GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Oxysterol 22(R)-Hydroxycholesterol Induces the Expression of the Bile Salt Export Pump through Nuclear Receptor Farsenoid X Receptor but Not Liver X Receptor

Department of Biological and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island

Oxysterols are intermediates in the synthesis of bile acids and steroid hormones from cholesterol and function as ligands for liver X receptor (LXR). Bile salt export pump (BSEP) is responsible for canalicular secretion of bile acids and is tightly regulated by its substrates bile acids through nuclear receptor farnesoid X receptor (FXR). In a microarray study using human hepatocytes, BSEP was markedly induced not only by chenodeoxycholic acid (CDCA) but also by oxysterol 22(R)-hydroxycholesterol [22(R)-OHC]. We hypothesized that the expression of BSEP was induced by oxysterols through activation of LXR. To test the hypothesis, human primary hepatocytes or hepatoma cells were treated with 22(R)-OHC, and expression of BSEP was determined. The level of BSEP mRNA was increased as much as 5-fold upon oxysterol induction. In contrast to our hypothesis, the oxysterol-induced up-regulation of BSEP is mediated through FXR but not LXR. BSEP promoter activity was markedly induced by 22(R)-OHC in the presence of FXR but not LXRs. Mutation of the FXR element IR1 in the BSEP promoter significantly reduced its ability to respond to oxysterol induction. To determine whether 22(R)-OHC and CDCA bind to similar structural features of FXR, site-directed mutagenesis was performed in the FXR ligand binding domain. Mutation of residues R331 and I352 abolished activation mediated by CDCA and 22(R)-OHC. In contrast, substitution of residues L340 and R351 differentiated CDCA- and 22(R)-OHC-mediated activation. In conclusion, oxysterol 22(R)-OHC functions as an FXR ligand to induce BSEP expression and differs in the binding with FXR from CDCA.

Address correspondence to: Ruitang Deng, Department of Biological and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Fogarty Hall, 41 Lower College Road, Kingston, RI 02881. E-mail: dengr{at}mail.uri.edu

This article has been cited by other articles:

				X. Song, R. Kaimal, B. Yan, and R. Deng Liver receptor homolog 1 transcriptionally regulates human bile salt export pump expression J. Lipid Res., May 1, 2008; 49(5): 973 - 984. [Abstract] [Full Text] [PDF]

				S.-Y. Cai, L. Xiong, C. G. Wray, N. Ballatori, and J. L. Boyer The farnesoid X receptor FXR{alpha}/NR1H4 acquired ligand specificity for bile salts late in vertebrate evolution Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2007; 293(3): R1400 - R1409. [Abstract] [Full Text] [PDF]

				C. J. Delvecchio, P. Bilan, K. Radford, J. Stephen, B. L. Trigatti, G. Cox, K. Parameswaran, and J. P. Capone Liver X Receptor Stimulates Cholesterol Efflux and Inhibits Expression of Proinflammatory Mediators in Human Airway Smooth Muscle Cells Mol. Endocrinol., June 1, 2007; 21(6): 1324 - 1334. [Abstract] [Full Text] [PDF]

				R. Deng, D. Yang, A. Radke, J. Yang, and B. Yan The Hypolipidemic Agent Guggulsterone Regulates the Expression of Human Bile Salt Export Pump: Dominance of Transactivation over Farsenoid X Receptor-Mediated Antagonism J. Pharmacol. Exp. Ther., March 1, 2007; 320(3): 1153 - 1162. [Abstract] [Full Text] [PDF]

				D. D. Moore, S. Kato, W. Xie, D. J. Mangelsdorf, D. R. Schmidt, R. Xiao, and S. A. Kliewer International Union of Pharmacology. LXII. The NR1H and NR1I Receptors: Constitutive Androstane Receptor, Pregnene X Receptor, Farnesoid X Receptor {alpha}, Farnesoid X Receptor beta, Liver X Receptor {alpha}, Liver X Receptor beta, and Vitamin D Receptor Pharmacol. Rev., December 1, 2006; 58(4): 742 - 759. [Abstract] [Full Text] [PDF]

				S. Caron, B. Cariou, and B. Staels FXR: More than a Bile Acid Receptor? Endocrinology, September 1, 2006; 147(9): 4022 - 4024. [Full Text] [PDF]