High hepatic glutathione stores alleviate Fas-induced apoptosis in mice
High hepatic glutathione stores alleviate Fas-induced apoptosis in mice
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DOI：
10.1016/j.jhep.2006.11.015
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发表时间：
2007-05-01
影响因子：
25.7
通讯作者：
Pessayre, Dominique
中科院分区：
文献类型：
--
作者：
Cazanave, Sophie;Berson, Alain;Pessayre, Dominique
背景/目的：激动性Jo 2抗Fas抗体在小鼠中复制人暴发性肝炎。我们检验了增强肝脏谷胱甘肽（GSH）储备可能阻止Jo 2诱导的细胞凋亡的假设。方法：我们用正常饮食或富含硫氨基酸（SAA（+））的饮食喂养小鼠，使肝脏GSH增加63%，并用Jo 2攻击这些小鼠。SAA+饮食显着减弱了Jo 2介导的肝GSH减少和细胞质和线粒体中氧化型谷胱甘肽（GSSG）/GSH比值的增加。SAA（+）饮食防止蛋白激酶Czeta（PKC zeta）和p47（phox）磷酸化、Yes活化、Fas酪氨酸磷酸化、Bid截短、Bax和细胞色素c易位、线粒体膜电位崩溃、半胱天冬酶活化、DNA片段化、肝细胞凋亡和Jo 2给药后小鼠致死。SAA+饮食的保护作用被小剂量的佛尔酮消除，使肝脏GSH降低到正常饮食小鼠中观察到的水平。相反，GSH单乙酯的管理后，乔2管理防止肝脏GSH消耗和衰减的毒性在小鼠喂养与正常diet.Conclusions：SAA（+）的饮食保持GSSG/GSH的比例，并防止PKC zeta和p47（phox）磷酸化，是激活，Fas酪氨酸磷酸化，线粒体透化，Fas刺激后肝细胞凋亡。GSH单乙酯也是保护性的，提示可能的临床应用。(C)2006年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background/Aims: The agonistic Jo2 anti-Fas antibody reproduces human fulminant hepatitis in mice. We tested the hypothesis that enhancing hepatic glutathione (GSH) stores may prevent Jo2-induced apoptosis.Methods: We fed mice with a normal diet or a sulfur amino acid-enriched (SAA(+)) diet increasing hepatic GSH by 63%, and challenged these mice with Jo2.Results: The SAA+ diet markedly attenuated the Jo2-mediated decrease in hepatic GSH and the increase in the oxidized glutathione (GSSG)/GSH ratio in cytosol and mitochondria. The SAA(+) diet prevented protein kinase Czeta (PKC zeta) and p47(phox) phosphorylations, Yes activation, Fas-tyrosine phosphorylation, Bid truncation, Bax, and cytochrome c translocations, the mitochondrial membrane potential collapse, caspase activation, DNA fragmentation, hepatocyte apoptosis, and mouse lethality after Jo2 administration. The protective effect of the SAA+ diet was abolished by a small dose of phorone decreasing hepatic GSH back to the levels observed in mice fed the normal diet. Conversely, administration of GSH monoethyl ester after Jo2 administration prevented hepatic GSH depletion and attenuated toxicity in mice fed with the normal diet.Conclusions: The SAA(+) diet preserves GSSG/GSH ratios, and prevents PKC zeta and p47(phox) phosphorylations, Yes activation, Fas-tyrosine phosphorylation, mitochondrial permeabilization, and hepatic apoptosis after Fas stimulation. GSH monoethyl ester is also protective, suggesting possible clinical applications. (C) 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.