Metabolic depletion of ATP by fructose inversely controls CD95- and tumor necrosis factor receptor 1-mediated hepatic apoptosis.
Metabolic depletion of ATP by fructose inversely controls CD95- and tumor necrosis factor receptor 1-mediated hepatic apoptosis.
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DOI：
10.1084/jem.191.11.1975
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发表时间：
2000-06-05
期刊：
影响因子：
--
通讯作者：
Wendel A
中科院分区：
文献类型：
--
作者：
Latta M;Künstle G;Leist M;Wendel A
肝细胞凋亡在几种形式的肝脏疾病中至关重要。在这里，我们研究了在不同的小鼠肝损伤模型是否以及如何代谢诱导的肝细胞ATP水平的变化控制受体介导的细胞凋亡。ATP耗尽无论是在原代肝细胞或在体内的各种磷酸捕获碳水化合物，如果糖。在肿瘤坏死因子（TNF）受体或CD95活化后，定量肝细胞凋亡和肝损伤的程度。TNF诱导的细胞死亡在ATP耗竭的肝细胞培养物中被完全阻断，而CD95介导的细胞凋亡被增强。同样，急性肿瘤坏死因子诱导的肝损伤小鼠完全抑制ATP耗竭与酮己糖，而CD95介导的肝毒性增强。ATP耗竭阻止线粒体细胞色素c释放，线粒体膜电位的损失，II型半胱天冬酶的激活，DNA片段化，和细胞溶解后暴露于TNF。细胞凋亡抑制的程度与ATP耗竭的严重程度相关，并且当通过增加细胞外磷酸盐浓度来补充ATP时，TNF诱导的细胞凋亡得以恢复。我们的研究表明，TNF诱导的肝细胞凋亡可以选择性地和可逆地阻断线粒体功能障碍的上游由酮己糖介导的ATP耗竭。
Hepatocyte apoptosis is crucial in several forms of liver disease. Here, we examined in different models of murine liver injury whether and how metabolically induced alterations of hepatocyte ATP levels control receptor-mediated apoptosis. ATP was depleted either in primary hepatocytes or in vivo by various phosphate-trapping carbohydrates such as fructose. After the activation of the tumor necrosis factor (TNF) receptor or CD95, the extent of hepatocyte apoptosis and liver damage was quantified. TNF-induced cell death was completely blocked in ATP-depleted hepatocyte cultures, whereas apoptosis mediated by CD95 was enhanced. Similarly, acute TNF-induced liver injury in mice was entirely inhibited by ATP depletion with ketohexoses, whereas CD95-mediated hepatotoxicity was enhanced. ATP depletion prevented mitochondrial cytochrome c release, loss of mitochondrial membrane potential, activation of type II caspases, DNA fragmentation, and cell lysis after exposure to TNF. The extent of apoptosis inhibition correlated with the severity of ATP depletion, and TNF-induced apoptosis was restored when ATP was repleted by increasing the extracellular phosphate concentration. Our study demonstrates that TNF-induced hepatic apoptosis can be selectively and reversibly blocked upstream of mitochondrial dysfunction by ketohexose-mediated ATP depletion.
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DOI：
10.1084/jem.188.5.979
发表时间：
1998-09-07
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Ferrari D;Stepczynska A;Los M;Wesselborg S;Schulze-Osthoff K
通讯作者：
Schulze-Osthoff K
影响因子：
19
作者：
Green, D;Kroemer, G
通讯作者：
Kroemer, G
影响因子：
--
作者：
GORES, GJ;NIEMINEN, AL;LEMASTERS, JJ
通讯作者：
LEMASTERS, JJ
影响因子：
29.4
作者：
DICKSON, RC;BRONK, SF;GORES, GJ
通讯作者：
GORES, GJ
影响因子：
6
作者：
Hampton, MB;Orrenius, S
通讯作者：
Orrenius, S