Defective TNF-alpha-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice.
Defective TNF-alpha-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice.
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酸性鞘磷脂酶敲除小鼠中缺陷性 TNF-α 介导的肝细胞凋亡和肝损伤。
DOI：
10.1172/jci16010
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发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Fernandez-Checa,JoseC
中科院分区：
文献类型：
--
作者：
Garcia-Ruiz,Carmen;Colell,Anna;Mari,Montserrat;Morales,Albert;Calvo,Maria;Enrich,Carlos;Fernandez-Checa,JoseC
本研究探讨了酸性鞘磷脂酶（ASMase）在TNF-α介导的肝细胞凋亡中的作用。耗尽线粒体谷胱甘肽（mGSH）的培养肝细胞对TNF-α变得敏感，在线粒体膜去极化、细胞色素释放和caspase激活之前经历时间依赖性凋亡细胞死亡。环孢菌素A治疗可使mGSH耗竭的肝细胞免于TNF-α诱导的细胞死亡。相比之下，ASMase缺陷的mGSH耗尽肝细胞对TNF-α介导的细胞死亡具有抗性，但对外源性ASMase敏感。此外，尽管半乳糖胺预处理的ASMase +/+小鼠体内给予TNF-α或LPS会引起肝损伤，但ASMase-/-小鼠表现出最小的肝细胞损伤。为了分析ASMase的需求，我们评估了葡萄糖神经酰胺合成酶抑制对TNF-α介导的细胞凋亡的影响。这种方法可以抑制TNF-α产生鞘糖脂，保护mGSH耗尽的ASMase +/+肝细胞免受TNF-α的影响，尽管TNF-α刺激的神经酰胺形成增加。为了进一步测试鞘糖脂的参与，我们专注于神经节苷脂GD 3（GD 3），因为它通过与线粒体相互作用在细胞凋亡中发挥作用。通过激光扫描共聚焦显微镜分析GD 3的细胞再分布显示GD 3靶向ASMase +/+肝细胞中的线粒体，但不靶向ASMase-/-肝细胞中的线粒体。然而，用外源性ASMase处理ASMase-/-肝细胞诱导GD 3和线粒体的共定位。因此，ASMase通过促进鞘糖脂的线粒体靶向作用，促进TNF-α诱导的肝细胞凋亡。
This study addressed the contribution of acidic sphingomyelinase (ASMase) in TNF-α–mediated hepatocellular apoptosis. Cultured hepatocytes depleted of mitochondrial glutathione (mGSH) became sensitive to TNF-α, undergoing a time-dependent apoptotic cell death preceded by mitochondrial membrane depolarization, cytochromecrelease, and caspase activation. Cyclosporin A treatment rescued mGSH-depleted hepatocytes from TNF-α–induced cell death. In contrast, mGSH-depleted hepatocytes deficient in ASMase were resistant to TNF-α–mediated cell death but sensitive to exogenous ASMase. Furthermore, although in vivo administration of TNF-α or LPS to galactosamine-pretreatedASMase+/+mice caused liver damage,ASMase–/–mice exhibited minimal hepatocellular injury. To analyze the requirement of ASMase, we assessed the effect of glucosylceramide synthetase inhibition on TNF-α–mediated apoptosis. This approach, which blunted glycosphingolipid generation by TNF-α, protected mGSH-depletedASMase+/+hepatocytes from TNF-α despite enhancement of TNF-α–stimulated ceramide formation. To further test the involvement of glycosphingolipids, we focused on ganglioside GD3 (GD3) because of its emerging role in apoptosis through interaction with mitochondria. Analysis of the cellular redistribution of GD3 by laser scanning confocal microscopy revealed the targeting of GD3 to mitochondria inASMase+/+but not inASMase–/–hepatocytes. However, treatment ofASMase–/–hepatocytes with exogenous ASMase induced the colocalization of GD3 and mitochondria. Thus, ASMase contributes to TNF-α–induced hepatocellular apoptosis by promoting the mitochondrial targeting of glycosphingolipids.
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影响因子：
3.5
作者：
Giammarioli, AM;Garofalo, T;Malorni, W
通讯作者：
Malorni, W
DOI：
10.1172/jci16127
发表时间：
2002-07
期刊：
The Journal of clinical investigation
影响因子：
--
作者：
R. Kolesnick
通讯作者：
R. Kolesnick
神经酰胺诱导分离的线粒体释放细胞色素 c。
DOI：
10.1042/bss0660027
发表时间：
1999
期刊：
Biochemical Society symposium
影响因子：
--
作者：
Christoph Richter;P. Ghafourifar
通讯作者：
P. Ghafourifar
影响因子：
29.4
作者：
Colell, A;Gargía-Ruiz, C;Fernández-Checa, JC
通讯作者：
Fernández-Checa, JC
影响因子：
15.9
作者：
GARCIARUIZ, C;MORALES, A;FERNANDEZCHECA, JC
通讯作者：
FERNANDEZCHECA, JC