title: Autophagy confers resistance to lipopolysaccharide-induced mouse hepatocyte injury.
abstract: During sepsis, bacterial products, particularly LPS, trigger injury in organs such as the liver. This common condition remains largely untreatable, in part due to a lack of understanding of how high concentrations of LPS cause cellular injury. In the liver, the lysosomal degradative pathway of autophagy performs essential hepatoprotective functions and is induced by LPS. We, therefore, examined whether hepatocyte autophagy protects against liver injury from septic levels of LPS. Mice with an inducible hepatocyte-specific knockout of the critical autophagy gene Atg7 were examined for their sensitivity to high-dose LPS. Increased liver injury occurred in knockout mice, as determined by significantly increased serum alanine aminotransferase levels, histological evidence of liver injury, terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling, and effector caspase-3 and -7 activation. Hepatic inflammation and proinflammatory cytokine induction were unaffected by the decrease in hepatocyte autophagy. Although knockout mice had normal NF-κB signaling, hepatic levels of Akt1 and Akt2 phosphorylation in response to LPS were decreased. Cultured hepatocytes from knockout mice displayed a generalized defect in Akt signaling in response to multiple stimuli, including LPS, TNF, and IL-1β. Akt activation mediates hepatocyte resistance to TNF cytotoxicity, and anti-TNF antibodies significantly decreased LPS-induced liver injury in knockout mice, indicating that the loss of autophagy sensitized to TNF-dependent liver damage. Hepatocyte autophagy, therefore, protects against LPS-induced liver injury. Conditions such as aging and steatosis that impair hepatic autophagy may predispose to poor outcomes from sepsis through this mechanism.
authors.affiliation: Department of Medicine and the Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York;
authors.forename: Gadi
authors.initials: G
authors.lastname: Lalazar
authors.affiliation: Department of Medicine and the Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York;
authors.forename: Ghulam
authors.initials: G
authors.lastname: Ilyas
authors.affiliation: Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Department of Biochemistry, Sargodha Medical College, University of Sargodha, Sargodha, Pakistan; and.
authors.forename: Shoaib Ahmad
authors.initials: SA
authors.lastname: Malik
authors.affiliation: Department of Medicine and the Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York;
authors.forename: Kun
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Medicine and the Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York;
authors.forename: Enpeng
authors.initials: E
authors.lastname: Zhao
authors.affiliation: Department of Medicine and the Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York;
authors.forename: Mohammad
authors.initials: M
authors.lastname: Amir
authors.affiliation: Department of Medicine and the Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York;
authors.forename: Yu
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Tanaka
authors.affiliation: Department of Medicine and the Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York; Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; mark.j.czaja@emory.edu.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Czaja
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000502:physiology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; apoptosis; liver; sepsis; tumor necrosis factor