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

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: dmd.108.025155v1 37/3/469    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 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 Han, S. Articles by Chiang, J. Y. L. Search for Related Content PubMed PubMed Citation Articles by Han, S. Articles by Chiang, J. Y. L.

Mechanism of Vitamin D Receptor Inhibition of Cholesterol 7-Hydroxylase Gene Transcription in Human Hepatocytes

Department of Integrative Medical Sciences, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, Rootstown, Ohio

Lithocholic acid (LCA) is a potent endogenous vitamin D receptor (VDR) ligand. In cholestasis, LCA levels increase in the liver and intestine. The objective of this study is to test the hypothesis that VDR plays a role in inhibiting cholesterol 7-hydroxylase (CYP7A1) gene expression and bile acid synthesis in human hepatocytes. Immunoblot analysis has detected VDR proteins in the nucleus of the human hepatoma cell line HepG2 and human primary hepatocytes. 1, 25-Dihydroxy-vitamin D₃ or LCA acetate-activated VDR inhibited CYP7A1 mRNA expression and bile acid synthesis, whereas small interfering RNA to VDR completely abrogated VDR inhibition of CYP7A1 mRNA expression in HepG2 cells. Electrophoretic mobility shift assay and mutagenesis analyses have identified the negative VDR response elements that bind VDR/retinoid X receptor in the human CYP7A1 promoter. Mammalian two-hybrid, coimmunoprecipitation, glutathione S-transferase pull-down, and chromatin immunoprecipitation assays show that ligand-activated VDR specifically interacts with hepatocyte nuclear factor 4 (HNF4) to block HNF4 interaction with coactivators or to compete with HNF4 for coactivators or to compete for binding to CYP7A1 chromatin, which results in the inhibition of CYP7A1 gene transcription. This study shows that VDR is expressed in human hepatocytes and may play a critical role in the inhibition of bile acid synthesis, thus protecting liver cells during cholestasis.

This article has been cited by other articles:

				J. Y. L. Chiang Bile acids: regulation of synthesis J. Lipid Res., October 1, 2009; 50(10): 1955 - 1966. [Abstract] [Full Text] [PDF]

				J. D. Amaral, R. J. S. Viana, R. M. Ramalho, C. J. Steer, and C. M. P. Rodrigues Bile acids: regulation of apoptosis by ursodeoxycholic acid J. Lipid Res., September 1, 2009; 50(9): 1721 - 1734. [Abstract] [Full Text] [PDF]