Bile acid-induced TGR5-dependent c-Jun-N terminal kinase activation leads to enhanced caspase 8 activation in hepatocytes.
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.
Yang
Jong In
JI
Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul 110-744, Republic of Korea.
Yoon
Jung-Hwan
JH
Myung
Sun Jung
SJ
Gwak
Geum-Youn
GY
Kim
Won
W
Chung
Goh Eun
GE
Lee
Sung Hee
SH
Lee
Soo-Mi
SM
Kim
Chung Yong
CY
Lee
Hyo-Suk
HS
D017209:Apoptosis; D001647:Bile Acids and Salts / Q000494:pharmacology*; D053181:Caspase 8 / Q000378:metabolism*; D045744:Cell Line, Tumor; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism; D004789:Enzyme Activation; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
D001647:Bile Acids and Salts; D053418:Death Domain Receptor Signaling Adaptor Proteins; C473772:GPBAR1 protein, human; D043562:Receptors, G-Protein-Coupled; D048031:JNK Mitogen-Activated Protein Kinases; D053181:Caspase 8