PMID- 12198651
OWN - NLM
STAT- MEDLINE
DCOM- 20020927
LR  - 20220311
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 36
IP  - 3
DP  - 2002 Sep
TI  - Effect of tauroursodeoxycholic acid on endoplasmic reticulum stress-induced 
      caspase-12 activation.
PG  - 592-601
AB  - 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.
FAU - Xie, Qing
AU  - Xie Q
AD  - Department of Medicine, Veterans Affairs Medical Center, Houston, TX 77030, USA.
FAU - Khaoustov, Vladimir I
AU  - Khaoustov VI
FAU - Chung, Charles C
AU  - Chung CC
FAU - Sohn, Joohyun
AU  - Sohn J
FAU - Krishnan, Bhuvaneswari
AU  - Krishnan B
FAU - Lewis, Dorothy E
AU  - Lewis DE
FAU - Yoffe, Boris
AU  - Yoffe B
LA  - eng
GR  - P30 AI36211/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Cholagogues and Choleretics)
RN  - 0 (Endoplasmic Reticulum Chaperone BiP)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (HSPA5 protein, human)
RN  - 516-35-8 (Taurochenodeoxycholic Acid)
RN  - 60EUX8MN5X (ursodoxicoltaurine)
RN  - 67526-95-8 (Thapsigargin)
RN  - EC 3.4.22.- (CASP12 protein, human)
RN  - EC 3.4.22.- (CASP3 protein, human)
RN  - EC 3.4.22.- (CASP7 protein, human)
RN  - EC 3.4.22.- (Caspase 12)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspase 7)
RN  - EC 3.4.22.- (Caspases)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Apoptosis/drug effects/physiology
MH  - Calcium/metabolism
MH  - Caspase 12
MH  - Caspase 3
MH  - Caspase 7
MH  - Caspases/*metabolism
MH  - Cell Line
MH  - Cholagogues and Choleretics/*pharmacology
MH  - Endoplasmic Reticulum/*metabolism
MH  - Endoplasmic Reticulum Chaperone BiP
MH  - Enzyme Activation/drug effects/physiology
MH  - Enzyme Inhibitors/pharmacology
MH  - Hepatocytes/cytology/enzymology/ultrastructure
MH  - Humans
MH  - Liver Diseases/drug therapy/metabolism
MH  - Microscopy, Electron
MH  - Mitochondria/metabolism
MH  - Taurochenodeoxycholic Acid/*pharmacology
MH  - Thapsigargin/pharmacology
EDAT- 2002/08/29 10:00
MHDA- 2002/09/28 04:00
CRDT- 2002/08/29 10:00
PHST- 2002/08/29 10:00 [pubmed]
PHST- 2002/09/28 04:00 [medline]
PHST- 2002/08/29 10:00 [entrez]
AID - S0270913902000642 [pii]
AID - 10.1053/jhep.2002.35441 [doi]
PST - ppublish
SO  - Hepatology. 2002 Sep;36(3):592-601. doi: 10.1053/jhep.2002.35441.