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Bile acid-induced TGR5-dependent c-Jun-N terminal kinase activation leads to enhanced caspase 8 activation in hepatocytes

Cited 50 time in Web of Science Cited 56 time in Scopus
Authors
Yang, Jong In; Yoon, Jung-Hwan; Myung, Sun Jung; Gwak, Geum-Youn; Kim, Won; Chung, Goh Eun; Lee, Sung Hee; Lee, Soo-Mi; Kim, Chung Yong; Lee, Hyo-Suk
Issue Date
2007-07-31
Publisher
Elsevier
Citation
Biochem Biophys Res Commun. 2007 Sep 14;361(1):156-61. Epub 2007 Jul 19.
Keywords
ApoptosisBile Acids and Salts/*pharmacologyCaspase 8/*metabolismCell Line, TumorDeath Domain Receptor Signaling Adaptor Proteins/metabolismEnzyme ActivationHepatocytes/cytology/drug effects/*enzymologyHumansJNK Mitogen-Activated Protein Kinases/*metabolismReceptors, 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
DOI
https://doi.org/10.1016/j.bbrc.2007.07.001
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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