title: Inactivation of Sirt1 in mouse livers protects against endotoxemic liver injury by acetylating and activating NF-κB.
abstract: Sirtuin 1 (Sirt1) is a deacetylase that regulates many cellular processes in the liver, and so far its role in endotoxemic liver injury is elusive. So we conditionally inactivate Sirt1 in murine hepatocytes to determine its role in d-galactosamine (GalN)/lipopolysaccharide (LPS)-induced liver damage, which is a well-established experimental model mimicking septic liver injury and fulminant hepatitis. Ablation of Sirt1 shows remarkable protection against GalN/LPS-induced liver injury, which is a result of enhanced NF-κB response because knockdown of RelA/p65 negates the protective effect of Sirt1 knockout. Mechanistically, NF-κB p65 is maintained in a hyperacetylated, DNA-binding competent state in tumor necrosis factor-α (TNF-α)-challenged albumin-Cre+(AlbCre+) hepatocytes. Transfection of hepatocytes with a recombinant acetylated p65 expression construct replicates the protection afforded by Sirt1 knockout. Transfection of AlbCre+hepatocytes with a recombinant wild-type Sirt1 construct, rather than a deacetylase-defective one, compromises NF-κB activation and resensitizes hepatocytes to TNF-α-induced apoptosis. Taken together, our results demonstrate that Sirt1 deacetylates p65 and compromises NF-κB activity in hepatocytes when confronted with LPS/TNF-α stimulation, leading to increased susceptibility to endotoxemic injury. These findings identify a possible protein effector to maneuver the hepatic NF-κB signaling pathway under inflammatory circumstances and a feasible way to increase hepatocellular resistance to endotoxin/TNF-α toxicity.
authors.affiliation: Department of Transplantation and Hepatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Cui
authors.affiliation: Department of Geriatric Cardiology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Transplantation Center of the Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Dong
authors.affiliation: The Central Laboratory of Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Longmei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Transplantation and Hepatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Tianfei
authors.initials: T
authors.lastname: Lu
authors.affiliation: Department of Transplantation and Hepatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Dawei
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Transplantation and Hepatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jiangjun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Transplantation and Hepatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Transplantation and Hepatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xia
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D004247:DNA / Q000378:metabolism; D019446:Endotoxemia / Q000378:metabolism* / Q000473:pathology; D005688:Galactosamine; D055785:Gene Knockdown Techniques; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019426:Integrases / Q000378:metabolism; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D020011:Protective Agents / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D020011:Protective Agents; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D004247:DNA; C045073:Cre recombinase; D019426:Integrases; D056564:Sirtuin 1