title: Uncoupling protein-2 (UCP2) induces mitochondrial proton leak and increases susceptibility of non-alcoholic steatohepatitis (NASH) liver to ischaemia-reperfusion injury.
abstract: BACKGROUND
  The mechanisms of progression from fatty liver to steatohepatitis and cirrhosis are not well elucidated. Mitochondrial dysfunction represents a key factor in the progression of non-alcoholic steatohepatitis (NASH) as mitochondria are the main cellular site of fatty acid oxidation, ATP synthesis and reactive oxygen species (ROS) production.
  
  
  OBJECTIVE
  (1) To evaluate the role of the uncoupling protein 2 in controlling mitochondrial proton leak and ROS production in NASH rats and humans; and (2) to assess the acute liver damage induced by ischaemia-reperfusion in rats with NASH.
  
  
  METHODS
  Mitochondria were extracted from the livers of NASH humans and rats fed a methionine and choline deficient diet. Proton leak, H(2)O(2) synthesis, reduced glutathione/oxidised glutathione, 4-hydroxy-2-nonenal (HNE)-protein adducts, uncoupling protein-2 (UCP2) expression and ATP homeostasis were evaluated before and after ischaemia-reperfusion injury.
  
  
  RESULTS
  NASH mitochondria exhibited an increased rate of proton leak due to upregulation of UCP2. These results correlated with increased production of mitochondrial hydrogen peroxide and HNE-protein adducts, and decreased hepatic ATP content that was not dependent on mitochondrial ATPase dysfunction. The application of an ischaemia-reperfusion protocol to these livers strongly depleted hepatic ATP stores, significantly increased mitochondrial ROS production and impaired ATPase activity. Livers from patients with NASH exhibited UCP2 over-expression and mitochondrial oxidative stress.
  
  
  CONCLUSIONS
  Upregulation of UCP2 in human and rat NASH liver induces mitochondrial uncoupling, lowers the redox pressure on the mitochondrial respiratory chain and acts as a protective mechanism against damage progression but compromises the liver capacity to respond to additional acute energy demands, such as ischaemia-reperfusion. These findings suggest that UCP2-dependent mitochondria uncoupling is an important factor underlying events leading to NASH and cirrhosis.
authors.affiliation: Institute of Internal Medicine, Department of Medical and Occupational Sciences, University of Foggia, Foggia, Italy. g.serviddio@unifg.it
authors.forename: G
authors.initials: G
authors.lastname: Serviddio
authors.forename: F
authors.initials: F
authors.lastname: Bellanti
authors.forename: R
authors.initials: R
authors.lastname: Tamborra
authors.forename: T
authors.initials: T
authors.lastname: Rollo
authors.forename: N
authors.initials: N
authors.lastname: Capitanio
authors.forename: A D
authors.initials: AD
authors.lastname: Romano
authors.forename: J
authors.initials: J
authors.lastname: Sastre
authors.forename: G
authors.initials: G
authors.lastname: Vendemiale
authors.forename: E
authors.initials: E
authors.lastname: Altomare
mesh_terms: D000208:Acute Disease; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000172:deficiency; D000328:Adult; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D018450:Disease Progression; D005234:Fatty Liver / Q000150:complications* / Q000378:metabolism; D005260:Female; D006801:Humans; D007473:Ion Channels / Q000378:metabolism / Q000502:physiology*; D008099:Liver / Q000098:blood supply* / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000209:etiology* / Q000378:metabolism; D000071246:Uncoupling Protein 2
chemical_list: D000447:Aldehydes; D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C000604389:UCP2 protein, human; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; C027576:4-hydroxy-2-nonenal