SIRT3-dependent deacetylation exacerbates acetaminophen hepatotoxicity
SIRT3-dependent deacetylation exacerbates acetaminophen hepatotoxicity
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DOI：
10.1038/embor.2011.121
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发表时间：
2011-08-01
期刊：
影响因子：
7.7
通讯作者：
Sack, Michael N.
中科院分区：
文献类型：
--
作者：
Lu, Zhongping;Bourdi, Mohammed;Sack, Michael N.
对乙酰氨基酚/对乙酰氨基酚诱导的肝衰竭是由活性代谢物与线粒体蛋白的结合及其破坏引起的，禁食会加剧肝衰竭。由于禁食促进SIRT 3介导的线粒体蛋白脱乙酰化和对乙酰氨基酚代谢物与赖氨酸残基结合，我们研究了脱乙酰化是否使小鼠易于发生毒性代谢物介导的线粒体蛋白破坏。我们表明，线粒体脱乙酰酶SIRT 3（-/-）小鼠保护对乙酰氨基酚肝毒性，线粒体醛脱氢酶2是直接SIRT 3底物，其脱乙酰化增加对乙酰氨基酚毒性代谢物结合和酶失活。因此，蛋白质脱乙酰化通过调节毒性代谢物与线粒体蛋白的结合来增强外源性肝损伤。
Acetaminophen/paracetamol-induced liver failure-which is induced by the binding of reactive metabolites to mitochondrial proteins and their disruption-is exacerbated by fasting. As fasting promotes SIRT3-mediated mitochondrial-protein deacetylation and acetaminophen metabolites bind to lysine residues, we investigated whether deacetylation predisposes mice to toxic metabolite-mediated disruption of mitochondrial proteins. We show that mitochondrial deacetylase SIRT3(-/-) mice are protected from acetaminophen hepatotoxicity, that mitochondrial aldehyde dehydrogenase 2 is a direct SIRT3 substrate, and that its deacetylation increases acetaminophen toxic-metabolite binding and enzyme inactivation. Thus, protein deacetylation enhances xenobiotic liver injury by modulating the binding of a toxic metabolite to mitochondrial proteins.