Reduced glutathione depletion causes necrosis and sensitization to tumor necrosis factor-α-induced apoptosis in cultured mouse hepatocytes

Nagai, Hidenari; Matsumaru, Katsuhiko; Feng, Guoping; Kaplowitz, Neil

doi:10.1053/jhep.2002.33995

Cited by 168 publications

(124 citation statements)

References 40 publications

(54 reference statements)

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“…The presence of the observed caspase cleavage and DNA laddering was lost as apoptosis progressed to necrosis in the same manner as we have observed at late time points in our previously reported investigation (6). Furthermore, the sensitization of hepatocytes to apoptosis via TNF-α by GSH depletion has previously been shown (47).…”

Section: Discussionsupporting

confidence: 85%

Diet Restriction Inhibits Apoptosis and HMGB1 Oxidation and Promotes Inflammatory Cell Recruitment during Acetaminophen Hepatotoxicity

Antoine

Williams

Kipar

et al. 2010

Mol Med

116

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Acetaminophen (APAP) overdose is a major cause of acute liver failure and serves as a paradigm to elucidate mechanisms, predisposing factors and therapeutic interventions. The roles of apoptosis and inflammation during APAP hepatotoxicity remain controversial. We investigated whether fasting of mice for 24 h can inhibit APAP-induced caspase activation and apoptosis through the depletion of basal ATP . We also investigated in fasted mice the critical role played by inhibition of caspasedependent cysteine 106 oxidation within high mobility group box-1 protein (HMGB1) released by ATP depletion in dying cells as a mechanism of immune activation. In fed mice treated with APAP, necrosis was the dominant form of hepatocyte death. However, apoptosis was also observed, indicated by K18 cleavage, DNA laddering and procaspase-3 processing. In fasted mice treated with APAP, only necrosis was observed. Inflammatory cell recruitment as a consequence of hepatocyte death was observed only in fasted mice treated with APAP or fed mice cotreated with a caspase inhibitor. Hepatic inflammation was also associated with loss in detection of serum oxidized-HMGB1. A significant role of HMGB1 in the induction of inflammation was confirmed with an HMGB1-neutralizing antibody. The differential response between fasted and fed mice was a consequence of a significant reduction in basal hepatic ATP, which prevented caspase processing, rather than glutathione depletion or altered APAP metabolism. Thus, the inhibition of caspase-driven apoptosis and HMGB1 oxidation by ATP depletion from fasting promotes an inflammatory response during drug-induced hepatotoxicity/liver pathology.

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Section: Discussionsupporting

confidence: 85%

Diet Restriction Inhibits Apoptosis and HMGB1 Oxidation and Promotes Inflammatory Cell Recruitment during Acetaminophen Hepatotoxicity

Antoine

Williams

Kipar

et al. 2010

Mol Med

116

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“…31 It is effective but not as potent as MnTBAP in most of the assays in this study, except for lipid peroxidation, perhaps reflecting that O 2 Ϫ is the most important ROS here, which is most effectively scavenged by MnTBAP. Previous studies had shown that depletion of glutathione sensitized hepatocytes to TNF-␣ killing 26,46 and thus demonstrated the contribution of peroxides in this setting. However, supplemental glutathione 46 or overexpression of catalase 47 did not inhibit TNF-␣ killing, indicating the involvement of other ROS species such as O 2 Ϫ , as supported by this study.…”

Section: Discussionmentioning

confidence: 90%

“…Analyses were conducted at various time points after the treatment. Apoptotic and necrotic death were determined as previously described 26 with modifications. Briefly, cells were costained with Hoechst 33342 (5 g/mL) and propidium iodide (1 g/mL) for 10 minutes and analyzed via digital microscopy.…”

Section: Methodsmentioning

confidence: 99%

Bid-dependent generation of oxygen radicals promotes death receptor activation-induced apoptosis in murine hepatocytes

et al. 2004

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Activation of tumor necrosis factor receptor 1 or Fas leads to the generation of reactive oxygen species, which are important to the cytotoxic effects of tumor necrosis factor ␣ (TNF-␣) or Fas ligand. However, how these radicals are generated following receptor ligation is not clear. Using primary hepatocytes, we found that TNF-␣ or anti-Fas antibodyinduced burst of oxygen radicals was mainly derived from the mitochondria. We discovered that Bid-a pro-death Bcl-2 family protein activated by ligated death receptors-was the main intracellular molecule signaling the generation of the radicals by targeting to the mitochondria and that the majority of oxygen radical production was dependent on Bid. Reactive oxygen species contributed to cell death and caspase activation by promoting FLICE-inhibitory protein degradation and mitochondrial release of cytochrome c. For the latter part, the oxygen radicals did not affect Bak oligomerization but instead promoted mitochondrial cristae reorganization and membrane lipid peroxidation. Antioxidants could reverse these changes and therefore protect against TNF-␣ or anti-Fas-induced apoptosis. In conclusion, our studies established the signaling pathway from death receptor engagement to oxygen radical generation and determined the mechanism by which reactive oxygen species contributed to hepatocyte apoptosis following death receptor activation. (HEPATOLOGY 2004;40:403-413.)

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“…But mitochondria are the predominant source of ROS. Depletion of reduced glutathione can sensitize cultured mouse hepatocytes to TNF-α-induced cell death in the absence of transcription inhibitor, suggesting that ROS play a critical role in TNF-α-induced-liver injury [25,26]. The critical role of ROS in TNF-α-induced-liver injury is further supported by the evidence that over-expression of thioredoxin, a small redox-active protein with antioxidant effects, significantly attenuates LPS/GalN-induced liver injury in mice [27].…”

Section: Rosmentioning

confidence: 99%

Dissection of the multiple mechanisms of TNF‐α‐induced apoptosis in liver injury

Ding

Yin

2004

J Cellular Molecular Medi

265

179

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Tumor necrosis factor (TNF)-α-induced hepatocyte apoptosis is implicated in a wide range of liver diseases including viral hepatitis, alcoholic hepatitis, ischemia/reperfusion liver injury, and fulminant hepatic failure. TNF-α exerts a variety of effects that are mediated mainly by TNF-receptor 1 (TNF-R1) in cell death. The activation of TNF-R1 leads to the activation of multiple apoptotic pathways involving the activation of the pro-death Bcl-2 family proteins, reactive oxygen species, C-Jun NH2-terminal kinase, cathepsin B, acidic sphingomyelinase and neutral sphingomyelinase. These pathways are closely interlinked and mainly act on mitochondria, which release the apoptogenic factors and other events, resulting in apoptosis. This article reviews the recent progress in the molecular mechanisms of TNF-α-induced apoptosis in hepatocytes, and discusses how these molecular findings are shaping our understanding of the pathogenesis of liver diseases and our strategy to develop novel therapeutics.

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Reduced glutathione depletion causes necrosis and sensitization to tumor necrosis factor-α-induced apoptosis in cultured mouse hepatocytes

Cited by 168 publications

References 40 publications

Diet Restriction Inhibits Apoptosis and HMGB1 Oxidation and Promotes Inflammatory Cell Recruitment during Acetaminophen Hepatotoxicity

Diet Restriction Inhibits Apoptosis and HMGB1 Oxidation and Promotes Inflammatory Cell Recruitment during Acetaminophen Hepatotoxicity

Bid-dependent generation of oxygen radicals promotes death receptor activation-induced apoptosis in murine hepatocytes

Dissection of the multiple mechanisms of TNF‐α‐induced apoptosis in liver injury

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