title: Steatotic livers are susceptible to normothermic ischemia-reperfusion injury from mitochondrial Complex-I dysfunction.
abstract: OBJECTIVE
  To assess the effects of ischemic preconditioning (IPC, 10-min ischemia/10-min reperfusion) on steatotic liver mitochondrial function after normothermic ischemia-reperfusion injury (IRI).
  
  
  METHODS
  Sixty male Sprague-Dawley rats were fed 8-wk with either control chow or high-fat/high-sucrose diet inducing > 60% mixed steatosis. Three groups (n = 10/group) for each dietary state were tested: (1) the IRI group underwent 60 min partial hepatic ischemia and 4 h reperfusion; (2) the IPC group underwent IPC prior to same standard IRI; and (3) sham underwent the same surgery without IRI or IPC. Hepatic mitochondrial function was analyzed by oxygraphs. Mitochondrial Complex-I, Complex-II enzyme activity, serum alanine aminotransferase (ALT), and histological injury were measured.
  
  
  RESULTS
  Steatotic-IRI livers had a greater increase in ALT (2476 ± 166 vs 1457 ± 103 IU/L, P < 0.01) and histological injury following IRI compared to the lean liver group. Steatotic-IRI demonstrated lower Complex-I activity at baseline [78.4 ± 2.5 vs 116.4 ± 6.0 nmol/(min.mg protein), P < 0.001] and following IRI [28.0 ± 6.2 vs 104.3 ± 12.6 nmol/(min.mg protein), P < 0.001]. Steatotic-IRI also demonstrated impaired Complex-I function post-IRI compared to the lean liver IRI group. Complex-II activity was unaffected by hepatic steatosis or IRI. Lean liver mitochondrial function was unchanged following IRI. IPC normalized ALT and histological injury in steatotic livers but had no effect on overall steatotic liver mitochondrial function or individual mitochondrial complex enzyme activities.
  
  
  CONCLUSIONS
  Warm IRI impairs steatotic liver Complex-I activity and function. The protective effects of IPC in steatotic livers may not be mediated through mitochondria.
authors.affiliation: Michael JJ Chu, Rakesh Premkumar, Anthony RJ Phillips, Adam SJR Bartlett, Department of Surgery, University of Auckland, Auckland 1142, New Zealand.
authors.forename: Michael Jj
authors.initials: MJ
authors.lastname: Chu
authors.affiliation: Michael JJ Chu, Rakesh Premkumar, Anthony RJ Phillips, Adam SJR Bartlett, Department of Surgery, University of Auckland, Auckland 1142, New Zealand.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Premkumar
authors.affiliation: Michael JJ Chu, Rakesh Premkumar, Anthony RJ Phillips, Adam SJR Bartlett, Department of Surgery, University of Auckland, Auckland 1142, New Zealand.
authors.forename: Anthony Jr
authors.initials: AJ
authors.lastname: Hickey
authors.affiliation: Michael JJ Chu, Rakesh Premkumar, Anthony RJ Phillips, Adam SJR Bartlett, Department of Surgery, University of Auckland, Auckland 1142, New Zealand.
authors.forename: Yannan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Michael JJ Chu, Rakesh Premkumar, Anthony RJ Phillips, Adam SJR Bartlett, Department of Surgery, University of Auckland, Auckland 1142, New Zealand.
authors.forename: Brett
authors.initials: B
authors.lastname: Delahunt
authors.affiliation: Michael JJ Chu, Rakesh Premkumar, Anthony RJ Phillips, Adam SJR Bartlett, Department of Surgery, University of Auckland, Auckland 1142, New Zealand.
authors.forename: Anthony Rj
authors.initials: AR
authors.lastname: Phillips
authors.affiliation: Michael JJ Chu, Rakesh Premkumar, Anthony RJ Phillips, Adam SJR Bartlett, Department of Surgery, University of Auckland, Auckland 1142, New Zealand.
authors.forename: Adam Sjr
authors.initials: AS
authors.lastname: Bartlett
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D059305:Diet, High-Fat; D019422:Dietary Sucrose; D004195:Disease Models, Animal; D015536:Down-Regulation; D042967:Electron Transport Complex I / Q000378:metabolism*; D019194:Ischemic Preconditioning / Q000379:methods*; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008930:Mitochondria, Liver / Q000201:enzymology; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000097:blood / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D013997:Time Factors
chemical_list: D019422:Dietary Sucrose; D000410:Alanine Transaminase; D042967:Electron Transport Complex I
keywords: Fatty liver; Hepatic steatosis; Ischemic preconditioning; Liver injury; Liver ischemia; Mitochondrial respiration; Oxidative phosphorylation