title: Cholestasis is associated with hepatic microvascular dysfunction and aberrant energy metabolism before and during ischemia-reperfusion.
abstract: OBJECTIVE
  The aim was to investigate the impact of ischemia-reperfusion (I/R) on intrahepatic oxidative stress, oxidative phosphorylation, and nucleotide metabolism in relation to liver damage and inflammation in cholestatic rats to elucidate the molecular mechanisms responsible for post-I/R pathogenesis during cholestasis.
  
  
  RESULTS
  Pre-I/R cholestatic livers exhibited mild hepatopathology in the form of oxidative/nitrosative stress, perfusion defects, necrosis and apoptosis, inflammation, and fibrosis. Plasma bilirubin concentration in cholestatic livers was 190 μM. I/R in cholestatic livers exacerbated hepatocellular damage and leukocyte infiltration. However, myeloperoxidase activity in neutrophils at 6 h reperfusion was not elevated in cholestatic livers compared to pre-I/R levels and to control (Ctrl) livers. At 6 h reperfusion, cholestatic livers exhibited severe histological damage, which was absent in Ctrl livers. Despite a lower antioxidative capacity after I/R, no cardiolipin peroxidation and equivalent reduced glutathione/oxidized glutathione ratios and Hsp70 levels were found in cholestatic livers versus Ctrls. Bilirubin acted as a potent and protective antioxidant. Postischemic resumption of oxidative phosphorylation in Ctrl livers proceeded rapidly and encompassed reactive hyperemia, which was significantly impaired in cholestatic livers owing to extensive vasoconstriction and perfusion defects. Normalization of intrahepatic energy status and nucleotide-based metabolic cofactors was delayed in cholestatic livers during reperfusion. Innovation and
  
  
  CONCLUSIONS
  Cholestatic livers possess sufficient antioxidative capacity to ameliorate radical-mediated damage during I/R. I/R-induced damage in cholestatic livers is predominantly caused by microvascular perfusion defects rather than exuberant oxidative/nitrosative stress. The forestalled rate of oxidative phophorylation and recovery of bioenergetic and possibly metabolic parameters during the early reperfusion phase are responsible for extensive liver damage.
authors.affiliation: Department of Experimental Surgery, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Jaap J
authors.initials: JJ
authors.lastname: Kloek
authors.forename: Xavier
authors.initials: X
authors.lastname: Maréchal
authors.forename: Jeroen
authors.initials: J
authors.lastname: Roelofsen
authors.forename: Riekelt H
authors.initials: RH
authors.lastname: Houtkooper
authors.forename: André B P
authors.initials: AB
authors.lastname: van Kuilenburg
authors.forename: Willem
authors.initials: W
authors.lastname: Kulik
authors.forename: Rick
authors.initials: R
authors.lastname: Bezemer
authors.forename: Rémi
authors.initials: R
authors.lastname: Nevière
authors.forename: Thomas M
authors.initials: TM
authors.lastname: van Gulik
authors.forename: Michal
authors.initials: M
authors.lastname: Heger
mesh_terms: D000818:Animals; D002779:Cholestasis / Q000378:metabolism*; D006224:Cricetinae; D004734:Energy Metabolism; D008099:Liver / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008833:Microcirculation; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism*