Document Detail

The bile acid glycochenodeoxycholate induces trail-receptor 2/DR5 expression and apoptosis.
MedLine Citation:
PMID:  11507096     Owner:  NLM     Status:  MEDLINE    
Toxic bile salts induce hepatocyte apoptosis by both Fas-dependent and -independent mechanisms. In this study, we examined the cellular mechanisms responsible for Fas-independent, bile acid-mediated apoptosis. HuH-7 cells, which are known to be Fas deficient, were stably transfected with the sodium-dependent bile acid transporting polypeptide. The toxic bile acid glycochenodeoxycholate (GCDC)-induced apoptosis in these cells in a time- and concentration-dependent manner. Apoptosis and mitochondrial cytochrome c release were inhibited by transfection with dominant negative FADD, CrmA transfection, or treatment with the selective caspase 8 inhibitor IETD-CHO. These observations suggested the Fas-independent apoptosis was also death receptor mediated. Reverse transcriptase-polymerase chain reaction demonstrated tumor necrosis factor-R1, tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-R1/DR4, -R2/DR5, and TRAIL, but not tumor necrosis factor-alpha expression by these cells. GCDC treatment increased expression of TRAIL-R2/DR5 mRNA and protein 10-fold while expression of TRAIL-R1 was unchanged. Furthermore, aggregation of TRAIL-R2/DR5, but not TRAIL-R1/DR4 was observed following GCDC treatment of the cells. Induction of TRAIL-R2/DR5 expression and apoptosis by bile acids provides new insights into the mechanisms of hepatocyte apoptosis and the regulation of TRAIL-R2/DR5 expression.
H Higuchi; S F Bronk; Y Takikawa; N Werneburg; R Takimoto; W El-Deiry; G J Gores
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2001-08-15
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  276     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2001 Oct 
Date Detail:
Created Date:  2001-10-15     Completed Date:  2001-12-04     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  38610-8     Citation Subset:  IM    
Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic, and Foundation, Rochester, Minnesota 55905, USA.
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MeSH Terms
Apoptosis Regulatory Proteins
Caspase 8
Caspase 9
Caspases / antagonists & inhibitors
Cytochrome c Group / metabolism
Dose-Response Relationship, Drug
Enzyme Inhibitors / pharmacology
Genes, Dominant
Genes, Reporter
Glycochenodeoxycholic Acid / metabolism*,  physiology*
Hepatocytes / metabolism
Luciferases / metabolism
Membrane Glycoproteins / metabolism
Mitochondria / metabolism
Models, Genetic
Plasmids / metabolism
Precipitin Tests
RNA, Messenger / metabolism
Receptors, TNF-Related Apoptosis-Inducing Ligand
Receptors, Tumor Necrosis Factor / biosynthesis*
Reverse Transcriptase Polymerase Chain Reaction
Subcellular Fractions
TNF-Related Apoptosis-Inducing Ligand
Time Factors
Tumor Cells, Cultured
Tumor Necrosis Factor-alpha / metabolism
Grant Support
Reg. No./Substance:
0/Apoptosis Regulatory Proteins; 0/Cytochrome c Group; 0/Enzyme Inhibitors; 0/Ligands; 0/Membrane Glycoproteins; 0/RNA, Messenger; 0/Receptors, TNF-Related Apoptosis-Inducing Ligand; 0/Receptors, Tumor Necrosis Factor; 0/TNF-Related Apoptosis-Inducing Ligand; 0/TNFRSF10B protein, human; 0/TNFSF10 protein, human; 0/Tumor Necrosis Factor-alpha; 640-79-9/Glycochenodeoxycholic Acid; EC 1.13.12.-/Luciferases; EC 3.4.22.-/CASP8 protein, human; EC 3.4.22.-/CASP9 protein, human; EC 3.4.22.-/Caspase 8; EC 3.4.22.-/Caspase 9; EC 3.4.22.-/Caspases

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