Oral N-acetylcysteine rescues lethality of hepatocyte-specific Gclc-knockout mice, providing a model for hepatic cirrhosis.
Oral N-acetylcysteine rescues lethality of hepatocyte-specific Gclc-knockout mice, providing a model for hepatic cirrhosis.
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DOI：
10.1016/j.jhep.2010.05.028
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发表时间：
2010-12
影响因子：
25.7
通讯作者：
Dalton TP
中科院分区：
文献类型：
--
作者：
Chen Y;Johansson E;Yang Y;Miller ML;Shen D;Orlicky DJ;Shertzer HG;Vasiliou V;Nebert DW;Dalton TP
某些肝脏疾病与谷胱甘肽 (GSH) 的消耗有关，谷胱甘肽是肝脏中的主要抗氧化剂。最近的一份关于 Gclch/h 小鼠的肝细胞特异性 Gclc（编码 GSH 合成限速酶催化亚基的基因）的报告显示了 GSH 在肝功能中的重要作用。 Gclch/h 小鼠出现严重脂肪变性，并在 1 个月内死于肝衰竭，原因是肝脏 GSH 消耗约 95%；线粒体是主要受影响的细胞器，表现出超微结构异常和功能受损。从出生后第 18 天开始，用饮用水中的 L-N-乙酰半胱氨酸 (NAC；10 g/L) 喂养 Gclch/h 小鼠。通过补充 NAC 来挽救 Gclch/h 小鼠至成年期。 NAC 补充线粒体 GSH 库并减轻线粒体损伤，同时减少肝脏脂肪变性；然而，获救小鼠的肝脏生化测试异常、肝细胞死亡和肝脏氧化应激仍然存在。 50天时，获救的Gclch/h小鼠的肝脏开始表现出纤维化特征，120天时观察到大结节性肝硬化。肝脏特异性标记物的免疫组织染色和肝细胞因子的表达谱表明，肝硬化结节中肝细胞的重新增殖涉及卵圆细胞的扩张。补充线粒体 GSH 并通过 NAC 恢复线粒体功能可防止因肝细胞 GSH 从头合成丧失而导致的死亡，从而使脂肪变性进展至慢性阶段。因此，通过补充 NAC，Gclch/h 小鼠提供了肝纤维化和肝硬化发展的模型。
Certain liver diseases have been associated with depletion of glutathione (GSH), the major antioxidant in liver. A recent report about Gclch/h mice having a hepatocyte-specific ablation of Gclc (the gene encoding the catalytic subunit of the rate-limiting enzyme in GSH synthesis) has shown an essential role of GSH in hepatic function. Gclch/h mice develop severe steatosis and die of liver failure within one month, due to ~95% depletion of hepatic GSH; mitochondria are the major affected organelles, displaying abnormal ultrastructure and impaired function. Gclch/h mice were fed with L-N-acetylcysteine (NAC; 10 g/L) in drinking water starting at postnatal day 18. Gclch/h mice were rescued by NAC supplementation to adulthood. NAC replenished the mitochondrial GSH pool and attenuated mitochondrial damage, accompanied with diminished hepatic steatosis; however, abnormal liver biochemical tests, hepatocytes death and hepatic oxidative stress persisted in the rescued mice. At age 50 days, the liver from rescued Gclch/h mice started to display characteristics of fibrosis, and at age 120 days, macronodular cirrhosis was observed. Immunohistostaining for liver-specific markers and the expression profile of hepatic cytokines indicated that the repopulation of hepatocytes in the cirrhotic nodules involves the expansion of oval cells. Replenishment of mitochondrial GSH and restoration of mitochondrial function by NAC prevent mortality caused by loss of hepatocyte GSH de novo synthesis, allowing the progression of steatosis to a chronic stage. Thus, with NAC supplementation, Gclch/h mice provide a model for the development of liver fibrosis and cirrhosis.
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影响因子：
3.2
作者：
Day, CP
通讯作者：
Day, CP
影响因子：
15.9
作者：
Leclercq, IA;Farrell, GC;Robertson, GR
通讯作者：
Robertson, GR
影响因子：
7.4
作者：
Circu, Magdalena L.;Rodriguez, Cynthia;Aw, Tak Yee
通讯作者：
Aw, Tak Yee
影响因子：
5.1
作者：
Lash, Lawrence H.
通讯作者：
Lash, Lawrence H.
影响因子：
2.9
作者：
Senft, AP;Dalton, TP;Shertzer, HG
通讯作者：
Shertzer, HG