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This Article Full Text Full Text (PDF) All Versions of this Article: 297/1/G90    most recent 00094.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Lam, I. P. Y. Articles by Chow, B. K. C. PubMed PubMed Citation Articles by Lam, I. P. Y. Articles by Chow, B. K. C.

LIVER AND BILIARY TRACT

Bile acids inhibit duodenal secretin expression via orphan nuclear receptor small heterodimer partner (SHP)

¹School of Biological Sciences, The University of Hong Kong, Hong Kong, China; ²Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea; ³Research, Central Texas Veterans Health Care System, Medicine and Systems Biology and Translational Medicine, Texas A & M Health Science Center, College of Medicine, Temple, Texas

Submitted 11 March 2009 ; accepted in final form 10 April 2009

Small heterodimer partner (SHP) is an orphan nuclear receptor in which gene expression can be upregulated by bile acids. It regulates its target genes by repressing the transcriptional activities of other nuclear receptors including NeuroD, which has been shown to regulate secretin gene expression. Here, we evaluated the regulation on duodenal secretin gene expression by SHP and selected bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA). In vitro treatment of CDCA or fexaramine elevated the SHP transcript level and occupancy on secretin promoter. The increase in the SHP level, induced by bile acid treatment or overexpression, reduced secretin gene expression, whereas this gene inhibitory effect was reversed by silencing of endogenous SHP. In in vivo studies, double-immunofluorescence staining demonstrated the coexpression of secretin and SHP in mouse duodenum. Feeding mice with 1% CA-enriched rodent chow resulted in upregulation of SHP and a concomitant decrease in secretin transcript and protein levels in duodenum compared with the control group fed with normal chow. A diet enriched with 5% cholestyramine led to a decrease in SHP level and a corresponding increase in secretin expression. Overall, this study showed that bile acids via SHP inhibit duodenal secretin gene expression. Because secretin is a key hormone that stimulates bile flow in cholangiocytes, this pathway thus provides a novel means to modulate secretin-stimulated choleresis in response to intraduodenal bile acids.

bile flow; choleresis; cholangiocyte; liver