title: Targeting cholesterol at different levels in the mevalonate pathway protects fatty liver against ischemia-reperfusion injury.
abstract: OBJECTIVE
  Liver steatosis enhances ischemia/reperfusion (I/R) injury and is considered a primary factor in graft failure after liver transplantation. Although previous reports have shown a role for qualitative steatosis (macrovesicular vs. microvesicular) in hepatic I/R injury, no studies have compared side by side the specific contribution of individual lipids accumulating in fatty liver to I/R damage.
  
  
  METHODS
  We used nutritional and genetic models of micro and macrovesicular fatty livers exhibiting specific lipid profiles to assess their susceptibility to normothermic I/R injury.
  
  
  RESULTS
  Unlike choline-deficient (CD) diet-fed mice, characterized by predominant liver triglycerides/free fatty acids (TG/FFA) accumulation, mice fed a cholesterol-enriched (HC) diet, which exhibited enhanced hepatic cholesterol loading in mitochondria, were highly sensitive to I/R-induced liver injury. In vivo two-photon confocal imaging revealed enhanced mitochondrial depolarization and generation of reactive oxygen species following hepatic I/R in HC-fed but not in CD-fed mice, consistent with decreased mitochondrial GSH (mGSH) observed in HC-fed mice. Moreover, ob/ob mice, characterized by increased hepatic TG, FFA, and cholesterol levels, were as sensitive to I/R-mediated liver injury as mice fed the HC diet. Livers from ob/ob mice displayed increased StAR expression and mitochondrial cholesterol accumulation, resulting in mGSH depletion. Interestingly, atorvastatin therapy or squalene synthase inhibition in vivo attenuated StAR overexpression, mitochondrial cholesterol loading, and mGSH depletion, protecting ob/ob mice from I/R-mediated liver injury.
  
  
  CONCLUSIONS
  Cholesterol accumulation, particularly in mitochondria, sensitizes to hepatic I/R injury, and thus represents a novel target to prevent the enhanced damage of steatotic livers to I/R-mediated damage.
authors.affiliation: Liver Unit and Centro de Investigaciones Biomédicas Esther Koplowitz, IMDiM, Hospital Clínic i Provincial and CIBEREHD, IDIBAPS, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Llacuna
authors.forename: Anna
authors.initials: A
authors.lastname: Fernández
authors.forename: Claudia Von
authors.initials: CV
authors.lastname: Montfort
authors.forename: Núria
authors.initials: N
authors.lastname: Matías
authors.forename: Laura
authors.initials: L
authors.lastname: Martínez
authors.forename: Francisco
authors.initials: F
authors.lastname: Caballero
authors.forename: Antoni
authors.initials: A
authors.lastname: Rimola
authors.forename: Montserrat
authors.initials: M
authors.lastname: Elena
authors.forename: Albert
authors.initials: A
authors.lastname: Morales
authors.forename: José C
authors.initials: JC
authors.lastname: Fernández-Checa
authors.forename: Carmen
authors.initials: C
authors.lastname: García-Ruiz
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D000069059:Atorvastatin; D002791:Cholesterol, Dietary / Q000493:pharmacokinetics*; D002794:Choline / Q000494:pharmacology; D002796:Choline Deficiency / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004791:Enzyme Inhibitors / Q000494:pharmacology; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors; D005234:Fatty Liver / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology*; D008082:Lipotropic Agents / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology*; D011812:Quinuclidines / Q000494:pharmacology; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D000924:Anticholesteremic Agents; D002791:Cholesterol, Dietary; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D008082:Lipotropic Agents; D011758:Pyrroles; D011812:Quinuclidines; C414830:YM 53601; D000069059:Atorvastatin; D013186:Farnesyl-Diphosphate Farnesyltransferase; D005978:Glutathione; D002794:Choline; D008798:Mevalonic Acid