Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine
Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine
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DOI：
10.1172/jci35722
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发表时间：
2009-06-01
影响因子：
15.9
通讯作者：
Perl, Andras
中科院分区：
文献类型：
--
作者：
Hanczko, Robert;Fernandez, David R.;Perl, Andras
尽管氧化应激与对乙酰氨基酚引起的急性肝衰竭以及慢性肝硬化和肝细胞癌（HCC）有关，但尚未发现共同的潜在代谢途径。最近的病例报告表明戊糖磷酸途径 (PPP) 酶转醛醇酶 (TAL；由 TALDO1 编码) 与儿童肝衰竭之间存在联系。在这里，我们发现 Taldo1(-/-) 和 Taldo1(+/-) 小鼠自发发展为 HCC，并且 Taldo1(-/-) 小鼠对对乙酰氨基酚诱导的肝衰竭的易感性增加。 Taldo1(-/-) 肝脏中氧化应激的特点是景天庚酮糖 7-磷酸的积累、无法回收核糖 5-磷酸用于氧化 PPP、NADPH 和谷胱甘肽水平耗尽以及脂质氢过氧化物的产生增加。此外，我们发现了肝线粒体的证据。功能障碍，表现为跨膜电位丧失、线粒体质量减少和 ATP/ADP 比率降低。 Taldo1(-/-)肝脏中β-连环蛋白磷酸化的减少和c-Jun表达的增强反映了对氧化应激的适应。 Taldo1(-/-)肝细胞在体外和体内均能抵抗CD95/Fas相关的细胞凋亡。值得注意的是，在 Taldo1(-/-) 小鼠中，终身服用强效抗氧化剂 N-乙酰半胱氨酸 (NAC) 可预防对乙酰氨基酚诱导的肝衰竭，恢复 Fas 依赖性肝细胞凋亡，并阻止肝癌发生。这些数据揭示了 TAL 介导的 PPP 分支对肝癌发生的保护作用，并确定 NAC 是治疗 TAL 缺乏性肝病的有希望的治疗方法。
Although oxidative stress has been implicated in acute acetaminophen-induced liver failure and in chronic liver cirrhosis and hepatocellular carcinoma (HCC), no common underlying metabolic pathway has been identified. Recent case reports suggest a link between the pentose phosphate pathway (PPP) enzyme transaldolase (TAL; encoded by TALDO1) and liver failure in children. Here, we show that Taldo1(-/-) and Taldo1(+/-) mice spontaneously developed HCC, and Taldo1(-/-) mice had increased susceptibility to acetaminophen-induced liver failure. Oxidative stress in Taldo1(-/-) livers was characterized by the accumulation of sedoheptulose 7-phosphate, failure to recycle ribose 5-phosphate for the oxidative PPP, depleted NADPH and glutathione levels, and increased production of lipid hydroperoxides. Furthermore, we found evidence of hepatic mitochondrial. dysfunction, as indicated by loss of transmembrane potential, diminished mitochondrial mass, and reduced ATP/ADP ratio. Reduced beta-catenin phosphorylation and enhanced c-Jun expression in Taldo1(-/-) livers reflected adaptation to oxidative stress. Taldo1(-/-) hepatocytes were resistant to CD95/Fas-mectiated apoptosis in vitro and in vivo. Remarkably, lifelong administration of the potent antioxidant N-acetylcysteine (NAC) prevented acetaminophen-induced liver failure, restored Fas-dependent hepatocyte apoptosis, and blocked hepatocarcinogenesis in Taldo1(-/-) mice. These data reveal a protective role for the TAL-mediated branch of the PPP against hepatocarcinogenesis and identify NAC as a promising treatment for liver disease in TAL deficiency.