Bile acids inhibit duodenal secretin expression via orphan nuclear receptor small heterodimer partner (SHP).
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.
School of Biological Sciences, The Univerity of Hong Kong, Pokfulam Rd., Hong Kong. bkcc@hkusua.hku.hk
Ian P Y
IP
Lam
Leo T O
LT
Lee
Hueng-Sik
HS
Choi
Gianfranco
G
Alpini
Billy K C
BK
Chow
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001555:Benzene Derivatives / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D002635:Chenodeoxycholic Acid / Q000008:administration & dosage / Q000378:metabolism*; D002792:Cholestyramine Resin / Q000008:administration & dosage; D019826:Cholic Acid / Q000378:metabolism*; D004032:Diet; D015536:Down-Regulation; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism*; D019858:Enteroendocrine Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D012633:Secretin / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
D051792:Basic Helix-Loop-Helix Proteins; D001555:Benzene Derivatives; D002635:Chenodeoxycholic Acid; D002792:Cholestyramine Resin; D019826:Cholic Acid; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D012633:Secretin; C474615:fexaramine; C099713:nuclear receptor subfamily 0, group B, member 2; C093564:Neurogenic differentiation factor 1