title: Uncoupling protein-2 deficiency provides protection in a murine model of endotoxemic acute liver failure.
abstract: OBJECTIVE
  Liver injury and cell death are prominent features in the pathogenesis of acute liver failure. Mitochondrial uncoupling protein 2 plays a controversial role in liver cell death through its involvement in the production of reactive oxygen species and adenosine triphosphate.
  
  
  METHODS
  This randomized controlled animal study was designed to investigate the exact role of uncoupling protein 2 in the pathogenesis of endotoxemic acute liver failure.
  
  
  METHODS
  Research laboratory of an academic institution. SUBJECTS, INTERVENTIONS, AND MEASUREMENTS: Uncoupling protein 2+/+ and uncoupling protein 2-/- mice were challenged with D-galactosamine (Gal, 720 mg/kg intraperitoneally) and Escherichia coli lipopolysaccharide (10 microg/kg intraperitoneally) and studied 6 hrs thereafter (n = 5 per group). Control mice received physiologic saline (n = 5 per group). Analysis included in vivo fluorescence microscopy of hepatic microcirculation and hepatocellular apoptosis as well as plasma malondialdehyde concentrations as reactive oxygen species-dependent lipid peroxidation product and hepatic adenosine triphosphate levels.
  
  
  RESULTS
  Administration of Gal-lipopolysaccharide in uncoupling protein 2+/+ mice caused systemic cytokine release and malondialdehyde production. Further, it provoked marked hepatic damage, characterized by intrahepatic leukocyte recruitment (10.5 +/- 1.3 n/mm2 vs. 3.3 +/- 0.5 n/mm2), microvascular perfusion failure (33.1% +/- 1.6% vs. 2.3% +/- 0.4%), and adenosine triphosphate depletion (3.4 +/- 0.9 micromol/g vs. 6.4 +/- 0.9 micromol/g). Furthermore, uncoupling protein +/+ mice revealed a huge rise in cell apoptosis, given by high numbers of hepatocytes exhibiting nuclear chromatin fragmentation (44.9 +/- 11.5 n/mm2 vs. 0.0 +/- 0.0 n/mm2) and cleaved caspase-3 expression (1.24 +/- 0.24 vs. 0.06 +/- 0.04). Liver injury was coexistent with enzyme release (alanine aminotransferase 442 +/- 126 U/L vs. 57 +/- 12 U/L) and necrotic cell death. Of interest, Gal-lipopolysaccharide-exposed uncoupling protein 2-/- mice exhibited higher rates of hepatocellular apoptosis (135.6 +/- 46.0 n/mm2) as well as cleaved caspase-3 expression (1.75 +/- 0.25), however, preserved hepatic adenosine triphosphate (6.4 +/- 1.7), milder perfusion failure (24.5 +/- 2.4) and decreased leukocyte recruitment (2.7 +/- 0.2), less necrotic injury, lower transaminase levels (340 +/- 91), and finally better survival rates.
  
  
  CONCLUSIONS
  The higher adenosine triphosphate availability in uncoupling protein 2-deficient mice might allow hepatocytes to undergo apoptosis as an energy-consuming mode of cell death, while at the same time cellular adenosine triphosphate levels seem to increase hepatic resistance against harmful effects upon Gal-lipopolysaccharide exposure. As net result, uncoupling protein 2 deficiency provided protection under endotoxemic stress conditions, underlining the significant role of the bioenergetic status in critical illness.
authors.affiliation: Institute for Experimental Surgery, University of Rostock, Rostock, Germany.
authors.forename: Khoi
authors.initials: K
authors.lastname: Le  Minh
authors.forename: Angela
authors.initials: A
authors.lastname: Kuhla
authors.forename: Kerstin
authors.initials: K
authors.lastname: Abshagen
authors.forename: Thomas
authors.initials: T
authors.lastname: Minor
authors.forename: Judith
authors.initials: J
authors.lastname: Stegemann
authors.forename: Saleh
authors.initials: S
authors.lastname: Ibrahim
authors.forename: Christian
authors.initials: C
authors.lastname: Eipel
authors.forename: Brigitte
authors.initials: B
authors.lastname: Vollmar
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000150:complications*; D007473:Ion Channels / Q000172:deficiency*; D017114:Liver Failure, Acute / Q000209:etiology* / Q000517:prevention & control*; D051379:Mice; D024101:Mitochondrial Proteins / Q000172:deficiency*; D000071246:Uncoupling Protein 2
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2