title: Apoptosis and necrosis in the liver: a tale of two deaths?
abstract: Death of hepatocytes and other hepatic cell types is a characteristic feature of liver diseases as diverse as cholestasis, viral hepatitis, ischemia/reperfusion, liver preservation for transplantation and drug/toxicant-induced injury. Cell death typically follows one of two patterns: oncotic necrosis and apoptosis. Necrosis is typically the consequence of acute metabolic perturbation with ATP depletion as occurs in ischemia/reperfusion and acute drug-induced hepatotoxicity. Apoptosis, in contrast, represents the execution of an ATP-dependent death program often initiated by death ligand/death receptor interactions, such as Fas ligand with Fas, which leads to a caspase activation cascade. A common event leading to both apoptosis and necrosis is mitochondrial permeabilization and dysfunction, although the mechanistic basis of mitochondrial injury may vary in different settings. Prevention of these modes of cell death is an important target of therapy, but controversies still exist regarding which mode of cell death predominates in various forms of liver disease and injury. Resolution of these controversies may come with the recognition that apoptosis and necrosis frequently represent alternate outcomes of the same cellular pathways to cell death, especially for cell death mediated by mitochondrial permeabilization. An understanding of processes leading to liver cell death will be important for development of effective interventions to prevent hepatocellular death leading to liver failure and to promote cancer and stellate cell death in malignancy and fibrotic disease.
authors.affiliation: Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Harmeet
authors.initials: H
authors.lastname: Malhi
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gores
authors.forename: John J
authors.initials: JJ
authors.lastname: Lemasters
mesh_terms: D000082:Acetaminophen / Q000633:toxicity; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D020169:Caspases / Q000627:therapeutic use; D002780:Cholestasis, Intrahepatic / Q000503:physiopathology; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007113:Immunity, Innate; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000502:physiology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000473:pathology; D016328:NF-kappa B / Q000502:physiology; D009336:Necrosis / Q000473:pathology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D015427:Reperfusion Injury / Q000276:immunology / Q000503:physiopathology; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D019014:fas Receptor / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D000082:Acetaminophen; D045304:Cytochromes c; D020169:Caspases