title: Fasting protects liver from ischemic injury through Sirt1-mediated downregulation of circulating HMGB1 in mice.
abstract: OBJECTIVE
  Fasting and calorie restriction are associated with a prolonged life span and an increased resistance to stress. The protective effects of fasting have been exploited for the mitigation of ischemic organ injury, yet the underlying mechanisms remain incompletely understood. Here, we investigated whether fasting protects liver against ischemia reperfusion (IR) through energy-preserving or anti-inflammatory mechanisms.
  
  
  METHODS
  Fasted C57BL6 mice were subjected to partial hepatic IR. Injury was assessed by liver enzymes and histology. Raw264-7 macrophage-like cells were investigated in vitro. Sirt1 and HMGB1 were inhibited using Ex527 and neutralizing antibodies, respectively.
  
  
  RESULTS
  Fasting for one, but not two or three days, protected from hepatic IR injury. None of the investigated energy parameters correlated with the protective effects. Instead, inflammatory responses were dampened in one-day-fasted mice and in starved macrophages. Fasting alone led to a reduction in circulating HMGB1 associated with cytoplasmic HMGB1 translocation, aggregate formation, and autophagy. Inhibition of autophagy re-elevated circulating HMGB1 and abolished protection in fasted mice, as did supplementation with HMGB1. In vitro, Sirt1 inhibition prevented HMGB1 translocation, leading to elevated HMGB1 in the supernatant. In vivo, Sirt1 inhibition abrogated the fasting-induced protection, but had no effect in the presence of neutralizing HMGB1 antibody.
  
  
  CONCLUSIONS
  Fasting for one day protects from hepatic IR injury via Sirt1-dependent downregulation of circulating HMGB1. The reduction in serum HMGB1 appears to be mediated by its engagement in the autophagic response. These findings integrate Sirt1, HMGB1, and autophagy into a common framework that underlies the anti-inflammatory properties of short-term fasting.
authors.affiliation: Swiss Hepato-Pancreatico-Biliary Center, Department of Surgery, University Hospital Zürich, CH-8091 Zürich, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rickenbacher
authors.affiliation: Swiss Hepato-Pancreatico-Biliary Center, Department of Surgery, University Hospital Zürich, CH-8091 Zürich, Switzerland.
authors.forename: Jae Hwi
authors.initials: JH
authors.lastname: Jang
authors.affiliation: Swiss Hepato-Pancreatico-Biliary Center, Department of Surgery, University Hospital Zürich, CH-8091 Zürich, Switzerland.
authors.forename: Perparim
authors.initials: P
authors.lastname: Limani
authors.affiliation: Swiss Hepato-Pancreatico-Biliary Center, Department of Surgery, University Hospital Zürich, CH-8091 Zürich, Switzerland.
authors.forename: Udo
authors.initials: U
authors.lastname: Ungethüm
authors.affiliation: Swiss Hepato-Pancreatico-Biliary Center, Department of Surgery, University Hospital Zürich, CH-8091 Zürich, Switzerland.
authors.forename: Kuno
authors.initials: K
authors.lastname: Lehmann
authors.affiliation: Swiss Hepato-Pancreatico-Biliary Center, Department of Surgery, University Hospital Zürich, CH-8091 Zürich, Switzerland.
authors.forename: Christian E
authors.initials: CE
authors.lastname: Oberkofler
authors.affiliation: Institute of Pathology, University Hospital Zürich, CH-8091 Zürich, Switzerland.
authors.forename: Achim
authors.initials: A
authors.lastname: Weber
authors.affiliation: Swiss Hepato-Pancreatico-Biliary Center, Department of Surgery, University Hospital Zürich, CH-8091 Zürich, Switzerland.
authors.forename: Rolf
authors.initials: R
authors.lastname: Graf
authors.affiliation: Swiss Hepato-Pancreatico-Biliary Center, Department of Surgery, University Hospital Zürich, CH-8091 Zürich, Switzerland.
authors.forename: Bostjan
authors.initials: B
authors.lastname: Humar
authors.affiliation: Swiss Hepato-Pancreatico-Biliary Center, Department of Surgery, University Hospital Zürich, CH-8091 Zürich, Switzerland. Electronic address: clavien@access.uzh.ch.
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Clavien
mesh_terms: D000818:Animals; D015536:Down-Regulation; D005215:Fasting; D024243:HMGB1 Protein / Q000097:blood* / Q000502:physiology; D007249:Inflammation / Q000517:prevention & control; D008099:Liver / Q000098:blood supply*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015427:Reperfusion Injury / Q000517:prevention & control*; D056564:Sirtuin 1 / Q000502:physiology*
chemical_list: D024243:HMGB1 Protein; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Anti-inflammatory; Autophagy; Fasting; HMGB1; Innate immunity; Kupffer cell; Liver ischemia; Sirtuin