title: Hepatocyte-specific high-mobility group box 1 deletion worsens the injury in liver ischemia/reperfusion: a role for intracellular high-mobility group box 1 in cellular protection.
abstract: High-mobility group box 1 (HMGB1) is an abundant chromatin-associated nuclear protein and released into the extracellular milieu during liver ischemia-reperfusion (I/R), signaling activation of proinflammatory cascades. Because the intracellular function of HMGB1 during sterile inflammation of I/R is currently unknown, we sought to determine the role of intracellular HMGB1 in hepatocytes after liver I/R. When hepatocyte-specific HMGB1 knockout (HMGB1-HC-KO) and control mice were subjected to a nonlethal warm liver I/R, it was found that HMGB1-HC-KO mice had significantly greater hepatocellular injury after I/R, compared to control mice. Additionally, there was significantly greater DNA damage and decreased chromatin accessibility to repair with lack of HMGB1. Furthermore, lack of hepatocyte HMGB1 led to excessive poly(ADP-ribose)polymerase 1 activation, exhausting nicotinamide adenine dinucleotide and adenosine triphosphate stores, exacerbating mitochondrial instability and damage, and, consequently, leading to increased cell death. We found that this was also associated with significantly more oxidative stress (OS) in HMGB1-HC-KO mice, compared to control. Increased nuclear instability led to a resultant increase in the release of histones with subsequently more inflammatory cytokine production and organ damage through activation of Toll-like receptor 9.
  
  
  CONCLUSIONS
  The lack of HMGB1 within hepatocytes leads to increased susceptibility to cellular death after OS conditions.
authors.affiliation: Department Of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: Hai
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department Of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: Gary W
authors.initials: GW
authors.lastname: Nace
authors.affiliation: Department Of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: Kerry-Ann
authors.initials: KA
authors.lastname: McDonald
authors.affiliation: Department Of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Tai
authors.affiliation: Department Of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: John R
authors.initials: JR
authors.lastname: Klune
authors.affiliation: Department Of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Rosborough
authors.affiliation: Department Of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ding
authors.affiliation: Department Of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA.|Center for Biologic Imaging, Department of Cell Biology, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Loughran
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Center for Biologic Imaging, Department of Cell Biology, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: Donna
authors.initials: D
authors.lastname: Beer-Stolz
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL.
authors.forename: Eugene B
authors.initials: EB
authors.lastname: Chang
authors.affiliation: Department Of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Billiar
authors.affiliation: Department Of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: Allan
authors.initials: A
authors.lastname: Tsung
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D019610:Cytoprotection; D004249:DNA Damage; D024243:HMGB1 Protein / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D008099:Liver / Q000098:blood supply*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009243:NAD / Q000378:metabolism; D018384:Oxidative Stress; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D015427:Reperfusion Injury / Q000209:etiology*; D051217:Toll-Like Receptor 9 / Q000502:physiology
chemical_list: D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D006657:Histones; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D009243:NAD; D000255:Adenosine Triphosphate; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1