Bile Acid-Induced TGR5-dependent c-Jun-N Terminal Kinase Activation Leads to Enhanced Caspase 8 Activation in Hepatocytes

Biochem Biophys Res Commun. 2007 Sep 14;361(1):156-61. doi: 10.1016/j.bbrc.2007.07.001. Epub 2007 Jul 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Bile Acids and Salts / pharmacology*
  • Caspase 8 / metabolism*
  • Cell Line, Tumor
  • Death Domain Receptor Signaling Adaptor Proteins / metabolism
  • Enzyme Activation
  • Hepatocytes / cytology
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology*
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Receptors, G-Protein-Coupled / metabolism*

Substances

  • Bile Acids and Salts
  • Death Domain Receptor Signaling Adaptor Proteins
  • GPBAR1 protein, human
  • Receptors, G-Protein-Coupled
  • JNK Mitogen-Activated Protein Kinases
  • Caspase 8