Targeting cholesterol at different levels in the mevalonate pathway protects fatty liver against ischemia-reperfusion injury

JOURNAL OF HEPATOLOGY

卷:54

Article

Llacuna, Laura^1,2  Fernandez, Anna^1,2  von Montfort, Claudia^1,2  Matias, Nuria^1,2  Martinez, Laura^1,2  Caballero, Francisco^1,2  Rimola, Antoni¹  Elena, Montserrat³  Morales, Albert^1,2  Fernandez-Checa, Jose C.¹  Garcia-Ruiz, Carmen^1,2 

[1] CSIC, Inst Invest Biomed Barcelona, Dept Cell Death & Proliferat, Barcelona 08036, Spain

[2] Hosp Clin Barcelona, Ctr Diagnost Biomed, E-08036 Barcelona, Spain

[3] Univ So Calif, Keck Sch Med, Res Ctr Alcohol Liver & Pancreat Dis, Los Angeles, CA 90033 USA

关键词: Hepatic steatosis;    Ischemia/reperfusion;    Liver transplantation;    Triglycerides;    Cholesterol;    Statins;    Squalene synthase;   

DOI  :  10.1016/j.jhep.2010.08.031

来源: Elsevier

【 摘 要 】

Background & Aims: 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. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

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