title: Chemical composition of hepatic lipids mediates reperfusion injury of the macrosteatotic mouse liver through thromboxane A(2).
abstract: OBJECTIVE
  Chemical composition of hepatic lipids is an evolving player in steatotic liver ischemia/reperfusion (I/R) injury. Thromboxane A(2) (TXA(2)) is a vasoactive pro-inflammatory lipid mediator derived from arachidonic acid (AA), an omega-6 fatty acid (Ω-6 FA). Reduced tolerance of the macrosteatotic liver to I/R may be related to increased TXA(2) synthesis due to the predominance of Ω-6 FAs.
  
  
  METHODS
  TXA(2) levels elicited by I/R in ob/ob and wild type mice were assessed by ELISA. Ob/ob mice were fed Ω-3 FAs enriched diet to reduce hepatic synthesis of AA and TXA(2) or treated with selective TXA(2) receptor blocker before I/R.
  
  
  RESULTS
  I/R triggered significantly higher hepatic TXA(2) production in ob/ob than wild type animals. Compared with ob/ob mice on regular diet, Ω-3 FAs supplementation markedly reduced hepatic AA levels before ischemia and consistently blunted hepatic TXA(2) synthesis after reperfusion. Sinusoidal perfusion and hepatocellular damage were significantly ameliorated despite downregulation of heme oxygenase-1. Hepatic transcript and protein levels of IL-1β and neutrophil recruitment were significantly diminished after reperfusion. Moreover, TXA(2) receptor blockage conferred similar protection without modification of the histological pattern of steatosis. A stronger protection was achieved in the steatotic compared with lean animals.
  
  
  CONCLUSIONS
  Enhanced I/R injury in the macrosteatotic liver is explained, at least partially, by TXA(2) mediated microcirculatory failure rather than size-related mechanical compression of the sinusoids by lipid droplets. TXA(2) blockage may be a simple strategy to include steatotic organs and overcome the shortage of donor organs for liver transplantation.
authors.affiliation: Swiss HPB (Hepato-Pancreatico-Biliary) and Transplant Center, Department of Surgery, University Hospital of Zurich, Switzerland.
authors.forename: Ashraf Mohammad
authors.initials: AM
authors.lastname: El-Badry
authors.forename: Jae-Hwi
authors.initials: JH
authors.lastname: Jang
authors.forename: Ahmed
authors.initials: A
authors.lastname: Elsherbiny
authors.forename: Claudio
authors.initials: C
authors.lastname: Contaldo
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Tian
authors.forename: Dimitri A
authors.initials: DA
authors.lastname: Raptis
authors.forename: Endre
authors.initials: E
authors.lastname: Laczko
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Moritz
authors.forename: Rolf
authors.initials: R
authors.lastname: Graf
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Clavien
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage; D005234:Fatty Liver / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry*; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000293:injuries* / Q000378:metabolism*; D008262:Macrophage Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008833:Microcirculation / Q000187:drug effects; D018375:Neutrophil Activation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors; D015427:Reperfusion Injury / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D013928:Thromboxane A2 / Q000378:metabolism*
chemical_list: D015525:Fatty Acids, Omega-3; D008055:Lipids; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D016718:Arachidonic Acid; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha