Document Detail


Physiological concentrations of bile acids down-regulate agonist induced secretion in colonic epithelial cells.
MedLine Citation:
PMID:  19583809     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In patients with bile acid malabsorption, high concentrations of bile acids enter the colon and stimulate Cl(-) and fluid secretion, thereby causing diarrhoea. However, deoxycholic acid (DCA), the predominant colonic bile acid, is normally present at lower concentrations where its role in regulating transport is unclear. Thus, the current study set out to investigate the effects of physiologically relevant DCA concentrations on colonic epithelial secretory function. Cl(-) secretion was measured as changes in short-circuit current across voltage-clamped T(84) cell monolayers. At high concentrations (0.5-1 mM), DCA acutely stimulated Cl(-) secretion but this effect was associated with cell injury, as evidenced by decreased transepithelial resistance (TER) and increased lactate dehydrogenase (LDH) release. In contrast, chronic (24 hrs) exposure to lower DCA concentrations (10-200 microM) inhibited responses to Ca(2+) and cAMP-dependent secretagogues without altering TER, LDH release, or secretagogue-induced increases in intracellular second messengers. Other bile acids - taurodeoxycholic acid, chenodeoxycholic acid and cholic acid - had similar antisecretory effects. DCA (50 microM) rapidly stimulated phosphorylation of the epidermal growth factor receptor (EGFr) and both ERK and p38 MAPKs (mitogen-activated protein kinases). The EGFr inhibitor, AG1478, and the protein synthesis inhibitor, cycloheximide, reversed the antisecretory effects of DCA, while the MAPK inhibitors, PD98059 and SB203580, did not. In summary, our studies suggest that, in contrast to its acute prosecretory effects at pathophysiological concentrations, lower, physiologically relevant, levels of DCA chronically down-regulate colonic epithelial secretory function. On the basis of these data, we propose a novel role for bile acids as physiological regulators of colonic secretory capacity.
Authors:
Niamh Keating; Magdalena S Mroz; Michael M Scharl; Christine Marsh; Gail Ferguson; Alan F Hofmann; Stephen J Keely
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-07-06
Journal Detail:
Title:  Journal of cellular and molecular medicine     Volume:  13     ISSN:  1582-4934     ISO Abbreviation:  J. Cell. Mol. Med.     Publication Date:  2009 Aug 
Date Detail:
Created Date:  2010-02-09     Completed Date:  2010-07-19     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101083777     Medline TA:  J Cell Mol Med     Country:  England    
Other Details:
Languages:  eng     Pagination:  2293-303     Citation Subset:  IM    
Affiliation:
Department of Molecular Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.
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MeSH Terms
Descriptor/Qualifier:
Animals
Bile Acids and Salts / physiology*
Cell Line
Colon / cytology,  secretion*
Down-Regulation*
Intestinal Mucosa / cytology,  secretion
Rats
Grant Support
ID/Acronym/Agency:
DK 64891/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Bile Acids and Salts

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