Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Bcl-2 family proteins consist of both antiapoptosis and pro-apoptosis members that regulate apoptosis typically at the mitochondrial level, mainly by controlling the release of cytochrome c and other mitochondrial apoptotic events. However, death signals mediated by Fas/TNF-R1 receptors can usually activate caspases directly, bypassing the need for mitochondria and escaping the regulation by Bcl-2 family proteins. Bid is a novel pro-apoptosis Bcl-2 family protein that is activated by Caspase 8 in response to Fas/TNF-R1 death receptor activation. Activated Bid is translocated to mitochondria and induces cytochrome c release, which in turn activates the downstream caspases. This Bid-mediated pathway is critical in hepatocyte apoptosis induced by Fas/TNF-R1 engagement, where direct activation of cytosolic caspase cascade seems inefficient. The dependence on Bid, and thus on the mitochondrial cytochrome c release, of hepatocyte apoptosis induced by the death receptors also renders it sensitive to the inhibitory regulation by the anti-apoptosis members of the Bcl-2 family proteins, such as Bcl-2 and Bcl-xL. Moreover, the revealing of this death pathway in hepatocytes is important to the understanding of the pathogenesis of a number of hepatic diseases such as hepatitis or endotoxemia-related hepatic failure.
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PMID:Bid, a critical mediator for apoptosis induced by the activation of Fas/TNF-R1 death receptors in hepatocytes. 1093 82

Derangement of the apoptotic program is considered an important cause of liver disease. It became clear that receptor-mediated apoptosis is of specific interest in this context, and CD95 and CD120a, both members of the tumor necrosis factor (TNF) receptor superfamily, are the most prominent cell death receptors involved. The death signal is induced upon ligand binding by recruitment of caspases via the adapter molecule MORT1/FADD to the receptor and their subsequent activation. To investigate the role of MORT1/FADD in hepatocyte apoptosis, we generated transgenic mice expressing liver-specific dominant negative mutant. Mice looked grossly normal; breeding and liver development were not different compared with wild-type littermates. Expression of the transgene completely protected animals from liver failure induced by the anti-Fas antibody Jo2, whereas control animals died as expected 3 to 6 hours after i.p. injection of 15 microg antibody from acute hemorrhagic liver failure. Histology demonstrated only moderate inflammatory changes in the transgenic animals, whereas severe hemorrhagic hepatitis was observed in controls. Similar results were obtained in a model of TNF-mediated liver failure, in which transgenic animals survived significantly better than wild-type animals. In conclusion, our experiments provide evidence that MORT1/FADD is indispensable for Fas and TNF-mediated hepatic injury. This is not only of great importance for targeting future therapies for liver disease but might also serve as an intriguing model to study other causes of liver injury.
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PMID:Dominant negative MORT1/FADD rescues mice from CD95 and TNF-induced liver failure. 1250 Jan 97

The TNFalpha receptor super-family consists of several members sharing a sequence homology in a unique function domain, the death domain, which is located in the intracellular portion of the receptor. These so-called death receptors, including Fas, TNF-R1 and TRAIL-R1/TRAIL-R2, are expressed on hepatocytes. When stimulated by their ligands, FasL, TNFalpha or TRAIL, respectively, the death receptors can activate multiple death domain-initiated apoptosis programs, including both extrinsic and intrinsic pathways. A cascade of caspases is activated, which cleave proteins important for the cell structure and function. Activation of the intrinsic pathway also leads to mitochondrial release of several apoptotic proteins and mitochondrial dysfunction, which kill the cell through both caspase-dependent and caspase-independent mechanisms. Death receptor-induced hepatocyte apoptosis contributes to the development of a number of liver diseases, including viral hepatitis, inflammatory hepatitis, Wilson's disease, alcoholic liver disease, endotoxiemia-induced liver failure and ischemia/reperfusion-induced liver damage. This article comprehensively reviews the mechanisms of induction and regulation of death receptor-initiated apoptosis in hepatocytes, examines how these molecular events affect our understanding of the pathogenesis of these diseases and further discusses the potential therapeutic application of the knowledge. We hope we can provide a cohesive and integrated perspective on the many aspects of these complicated processes.
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PMID:Death receptor activation-induced hepatocyte apoptosis and liver injury. 1452 81

Hepatocyte apoptosis has been documented in both clinical and experimental alcoholic liver disease. This study was undertaken to examine the effect of dietary zinc supplementation on hepatic apoptosis in mice subjected to a long-term ethanol exposure. Male adult 129S6 mice fed an ethanol-containing liquid diet for 6 months developed hepatitis, as indicated by neutrophil infiltration and elevation of hepatic keratinocyte chemoattractant (KC) and monocyte chemoattractant protein-1 (MCP-1) levels. Apoptotic cell death was detected in ethanol-exposed mice by a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and was confirmed by the increased activities of caspase-3 and -8. Zinc supplementation attenuated alcoholic hepatitis and reduced the number of TUNEL-positive cells in association with inhibition of caspase activities. Ethanol exposure caused oxidative stress, as indicated by reactive oxygen species accumulation, mitochondrial glutathione depletion, and decreased metallothionein levels in the liver, which were suppressed by zinc supplementation. The mRNA levels of tumor necrosis factor (TNF)-alpha, TNF-R1, FasL, Fas, Fas-associated factor-1, and caspase-3 in the liver were upregulated by ethanol exposure, which were attenuated by zinc supplementation. Zinc supplementation also prevented ethanol-elevated serum and hepatic TNF-alpha levels and TNF-R1 and Fas proteins in the liver. In conclusion, zinc supplementation prevented hepatocyte apoptosis in mice subjected to long-term ethanol exposure, and the action of zinc is likely through suppression of oxidative stress and death receptor-mediated pathways.
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PMID:Zinc supplementation inhibits hepatic apoptosis in mice subjected to a long-term ethanol exposure. 1837 24