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Structure-function analysis of the tertiary bile acid TUDCA for the resolution of endoplasmic reticulum stress in intestinal epithelial cells.
MedLine Citation:
PMID:  21605547     Owner:  NLM     Status:  Publisher    
Inflammatory bowel diseases (IBD) are chronically relapsing and immune-mediated disorders of the gastrointestinal tract. Endoplasmic reticulum (ER) stress mechanisms in the epithelium have been shown to be implemented into the pathogenesis of intestinal inflammation. Chemical chaperones have been shown to exhibit beneficial effects in various diseases associated with ER stress mechanisms by prohibiting the unfolded protein response (UPR). In a structure-function analysis, we tested the potential of the conjugated bile salt sodium tauroursodeoxycholate (TUDCA), naturally present in the small bowel, to resolve ER stress in intestinal epithelial cells. TUDCA efficiently inhibited the expression of UPR dependent genes like GRP78 triggered by the ER stressor tunicamycin in the small intestinal epithelial cell line Mode-K. TUDCA inhibited upstream signaling events in all three branches of the UPR cascade and diminished binding of UPR activated transcription factors to the grp78 promoter. A structure-function analysis revealed that UDCA but not its conjugation partner taurine, known as a chemical chaperone, is responsible for the inhibition of GRP78 induction and that UDCA is 10 times more effective than its taurine conjugate. This inhibitory effect was confirmed in a cell free assay, where TUDCA and UDCA but not taurine effectively inhibited the aggregation of thermally denatured BSA. We conclude that TUDCA and UDCA is a potent anti-aggregant for the resolution of ER stress in intestinal epithelial cells and should be considered as a potential drug target to resolve ER stress mechanisms underlying the pathology of IBD.
Emanuel Berger; Dirk Haller
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-5-14
Journal Detail:
Title:  Biochemical and biophysical research communications     Volume:  -     ISSN:  1090-2104     ISO Abbreviation:  -     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-5-24     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0372516     Medline TA:  Biochem Biophys Res Commun     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011. Published by Elsevier Inc.
Technische Universität München, Chair for Biofunctionality, ZIEL Research Center for Nutrition and Food Science, CDD Center for Diet and Disease, Gregor-Mendel-Str. 2, 85350 Freising-Weihenstephan, Germany.
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