Hepatocyte-specific Gclc deletion leads to rapid onset of steatosis with mitochondrial injury and liver failure
Hepatocyte-specific Gclc deletion leads to rapid onset of steatosis with mitochondrial injury and liver failure
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DOI：
10.1002/hep.21635
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发表时间：
2007-05-01
期刊：
影响因子：
13.5
通讯作者：
Dalton, Timothy P.
中科院分区：
文献类型：
--
作者：
Chen, Ying;Yang, Yi;Dalton, Timothy P.
氧化应激被认为是各种原因引起的肝损伤的重要介质。谷胱甘肽(GSH)是肝脏中的主要抗氧化剂，其耗竭与许多肝脏疾病有关。为了探讨GSH在体内的特殊作用，我们以GSH合成所必需的基因GCLC为靶点，使其两侧带有loxP位点，并利用白蛋白环化重组(Alb-Cre)转基因来干扰GCLC基因在肝细胞中的特异性。GCLC基因在出生后第14天(PND)内的缺失接近完成，GCLC蛋白的丢失在PND第21天完成。细胞GSH在PND14和PND28之间逐渐耗尽--尽管线粒体GSH的丢失没有那么严重。然而，肝脏超微结构检查显示线粒体形态发生了显著变化，这些变化伴随着体外线粒体功能和细胞ATP的显著下降，以及脂质过氧化的显著增加。这些小鼠的血浆五项生化测试与进行性严重的实质损伤一致。从PND21开始，肝细胞特异性GCLC基因敲除[GCLC(h/h)]小鼠的肝脏显示出肝脏脂肪变性的组织学特征；这包括炎症和肝细胞死亡，病情加重，导致小鼠在大约1个月大时死于肝功能衰竭的并发症。结论：GSH是肝功能所必需的，肝细胞GSH合成丧失可导致脂肪变性，线粒体损伤，肝功能衰竭。
Oxidative stress is considered to be a critical mediator in liver injury of various etiologies. Depletion of glutathione (GSH), the major antioxidant in liver, has been associated with numerous liver diseases. To explore the specific role of hepatic GSH in vivo, we targeted Gclc, a gene essential for GSH synthesis, so that it was flanked by loxP sites and used the albumin-cyclization recombination (Alb-Cre) transgene to disrupt the Gclc gene specifically in hepatocytes. Deletion within the Gclc gene neared completion by postnatal day (PND)14, and loss of GCLC protein was complete by PND21. Cellular GSH was progressively depleted between PND14 and PND28 - although loss of mitochondrial GSH was less severe. Nevertheless, ultrastructural examination of liver revealed dramatic changes in mitochondrial morphology, these alterations were accompanied by striking decreases in mitochondrial function in vitro, cellular ATP, and a marked increase in lipid peroxidation. Plasma fiver biochemistry tests from these mice were consistent with progressive severe parenchymal damage. Starting at PND21, livers from hepatocyte-specific Gclc knockout [Gclc(h/h)] mice showed histological features of hepatic steatosis; this included inflammation and hepatocyte death, which progressed in severity such that mice died at approximately I month of age due to complications from liver failure. Conclusion: GSH is essential for hepatic function and loss of hepatocyte GSH synthesis leads to steatosis with mitochondrial injury and hepatic failure.