title: Inhibition of hepatocyte autophagy increases tumor necrosis factor-dependent liver injury by promoting caspase-8 activation.
abstract: Recent investigations have demonstrated a complex interrelationship between autophagy and cell death. A common mechanism of cell death in liver injury is tumor necrosis factor (TNF) cytotoxicity. To better delineate the in vivo function of autophagy in cell death, we examined the role of autophagy in TNF-induced hepatic injury. Atg7Δhep mice with a hepatocyte-specific knockout of the autophagy gene atg7 were generated and cotreated with D-galactosamine (GalN) and lipopolysaccharide (LPS). GalN/LPS-treated Atg7Δhep mice had increased serum alanine aminotransferase levels, histological injury, numbers of TUNEL (terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling)-positive cells and mortality as compared with littermate controls. Loss of hepatocyte autophagy similarly sensitized to GalN/TNF liver injury. GalN/LPS injury in knockout animals did not result from altered production of TNF or other cytokines. Atg7Δhep mice had accelerated activation of the mitochondrial death pathway and caspase-3 and -7 cleavage. Increased cell death did not occur from direct mitochondrial toxicity or a lack of mitophagy, but rather from increased activation of initiator caspase-8 causing Bid cleavage. GalN blocked LPS induction of hepatic autophagy, and increased autophagy from beclin 1 overexpression prevented GalN/LPS injury. Autophagy, therefore, mediates cellular resistance to TNF toxicity in vivo by blocking activation of caspase-8 and the mitochondrial death pathway, suggesting that autophagy is a therapeutic target in TNF-dependent tissue injury.
authors.affiliation: Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: M
authors.initials: M
authors.lastname: Amir
authors.forename: E
authors.initials: E
authors.lastname: Zhao
authors.forename: L
authors.initials: L
authors.lastname: Fontana
authors.forename: H
authors.initials: H
authors.lastname: Rosenberg
authors.forename: K
authors.initials: K
authors.lastname: Tanaka
authors.forename: G
authors.initials: G
authors.lastname: Gao
authors.forename: M J
authors.initials: MJ
authors.lastname: Czaja
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D000071186:Beclin-1; D053181:Caspase 8 / Q000502:physiology*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D016207:Cytokines / Q000378:metabolism; D005688:Galactosamine / Q000009:adverse effects / Q000494:pharmacology; D022781:Hepatocytes / Q000473:pathology* / Q000502:physiology*; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000009:adverse effects / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D023421:Models, Animal; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects* / Q000494:pharmacology
chemical_list: D051017:Apoptosis Regulatory Proteins; C502661:Atg7 protein, mouse; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D016207:Cytokines; D008070:Lipopolysaccharides; D008869:Microtubule-Associated Proteins; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D053181:Caspase 8; D000071193:Autophagy-Related Protein 7