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Bile acid-induced TGR5-dependent c-Jun-N terminal kinase activation leads to enhanced caspase 8 activation in hepatocytes
Cited 51 time in
Web of Science
Cited 57 time in Scopus
- Authors
- Issue Date
- 2007-07-31
- Publisher
- Elsevier
- Citation
- Biochem Biophys Res Commun. 2007 Sep 14;361(1):156-61. Epub 2007 Jul 19.
- Keywords
- Apoptosis ; Bile Acids and Salts/*pharmacology ; Caspase 8/*metabolism ; Cell Line, Tumor ; Death Domain Receptor Signaling Adaptor Proteins/metabolism ; Enzyme Activation ; Hepatocytes/cytology/drug effects/*enzymology ; Humans ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Receptors, G-Protein-Coupled/*metabolism
- Abstract
- TGR5 is a novel G protein-coupled cell-surface bile acid receptor. In cholestasis, bile acids induce hepatocyte apoptosis by primarily activating death receptor-mediated signaling. We examined if bile acid-induced TGR5 activation is participating in bile acid-induced hepatocyte apoptosis. TGR5 expression and its responsiveness to bile acid were confirmed in human hepatocytes. TGR5 inhibition attenuated bile acid-induced caspase 8 activation, which resulted from reduced bile acid-induced caspase 8 recruited to a death-inducing signaling complex (DISC). Bile acid-induced c-Jun-N terminal kinase (JNK) activation was dependent on bile acid activation of TGR5. JNK formed complexes with caspase 8, which were reduced following bile acid treatment, but this reduction was prevented when TGR5 or JNK was inhibited. In conclusion, bile acids activate TGR5, which leads to JNK activation and reduced complex formation of JNK with caspase 8, thus facilitating caspase 8 recruitment to DISC. These observations suggest therapeutic applications for TGR5 signaling blockage in cholestasis.
- ISSN
- 0006-291X (Print)
- Language
- English
- URI
- http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17659258
https://hdl.handle.net/10371/24390
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