Effect of tauroursodeoxycholic acid on endoplasmic reticulum stress-induced caspase-12 activation

Hepatology. 2002 Sep;36(3):592-601. doi: 10.1053/jhep.2002.35441.

Abstract

Activation of death receptors and mitochondrial damage are well-described common apoptotic pathways. Recently, a novel pathway via endoplasmic reticulum (ER) stress has been reported. We assessed the role of tauroursodeoxycholic acid (TUDCA) in inhibition of caspase-12 activation and its effect on calcium homeostasis in an ER stress-induced model of apoptosis. The human liver-derived cell line, Huh7, was treated with thapsigargin (TG) to induce ER stress. Typical morphologic changes of ER stress preceded development of apoptotic changes, including DNA fragmentation and cleavage of poly (adenosine diphosphate-ribose) polymerase (PARP), as well as activation of caspase-3 and -7. Elevation of intracellular calcium levels without loss of mitochondrial membrane potential (MMP) was shown using Fluo-3/Fura-red labeling and flow cytometry, and confirmed by induction of Bip/GRP78, a calcium-dependent chaperon of ER lumen. These changes were accompanied by procaspase-12 processing. TUDCA abolished TG-induced markers of ER stress; reduced calcium efflux, induction of Bip/GRP78, and caspase-12 activation; and subsequently inhibited activation of effector caspases and apoptosis. In conclusion, we propose that mitochondria play a secondary role in ER-mediated apoptosis and that TUDCA prevents apoptosis by blocking a calcium-mediated apoptotic pathway as well as caspase-12 activation. This novel mechanism of TUDCA action suggests new intervention methods for ER stress-induced liver disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Calcium / metabolism
  • Caspase 12
  • Caspase 3
  • Caspase 7
  • Caspases / metabolism*
  • Cell Line
  • Cholagogues and Choleretics / pharmacology*
  • Endoplasmic Reticulum / metabolism*
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Enzyme Inhibitors / pharmacology
  • Hepatocytes / cytology
  • Hepatocytes / enzymology
  • Hepatocytes / ultrastructure
  • Humans
  • Liver Diseases / drug therapy
  • Liver Diseases / metabolism
  • Microscopy, Electron
  • Mitochondria / metabolism
  • Taurochenodeoxycholic Acid / pharmacology*
  • Thapsigargin / pharmacology

Substances

  • Cholagogues and Choleretics
  • Enzyme Inhibitors
  • Taurochenodeoxycholic Acid
  • ursodoxicoltaurine
  • Thapsigargin
  • CASP12 protein, human
  • CASP3 protein, human
  • CASP7 protein, human
  • Caspase 12
  • Caspase 3
  • Caspase 7
  • Caspases
  • Calcium