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

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• 作者：Laura Llacuna¹ ; ² ; Anna Ferná ; ndez¹ ; ² ; Claudia Von Montfort¹ ; ² ; Nú ; ria Mat&#xed ; as¹ ; ² ; Laura Mart&#xed ; nez¹ ; ² ; Francisco Caballero¹ ; ² ; Antoni Rimola¹ ; Montserrat Elena³ ; Albert Morales¹ ; ² ; ^† ; ; ^{amorales@clinic.ub.es} ; José ; C. Ferná ; ndez-Checa¹ ; ² ; ⁴ ; ^† ; ; ^{checa229@yahoo.com} ; Carmen Garc&#xed ; a-Ruiz¹ ; ² ; ^† ; ; ^{cgrbam@iibb.csic.es}
• 关键词：Hepatic steatosis ; Ischemia/reperfusion ; Liver transplantation ; Triglycerides ; Cholesterol ; Statins ; Squalene synthase
• 刊名：Journal of Hepatology
• 出版年：2011
• 出版时间：May 2011
• 年：2011
• 卷：54
• 期：5
• 页码：1002-1010
• 全文大小：2249 K

文摘

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.