Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide
Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide
复制标题
DOI：
10.1038/nm1539
复制
发表时间：
2007-02-01
期刊：
影响因子：
82.9
通讯作者：
Lang, Florian
中科院分区：
文献类型：
--
作者：
Lang, Philipp A.;Schenck, Marcus;Lang, Florian
肝豆状核变性是由Cu2+在细胞内积聚引起的，这会导致肝硬变，偶尔还会导致贫血。在这里，我们证明了Cu2+通过激活酸性鞘磷脂酶(ASM)和释放神经酰胺来触发肝细胞凋亡。ASM的遗传缺陷或药物抑制可阻止Cu2+诱导的肝细胞凋亡，并保护遗传上易患肝豆状核变性的大鼠急性肝细胞死亡、肝功能衰竭和早期死亡。Cu2+诱导白细胞分泌活化的ASM，导致神经酰胺在红细胞内释放和磷脂酰丝氨酸暴露在红细胞上，这一事件也可通过抑制ASM来阻止。暴露于磷脂酰丝氨酸可立即清除小鼠血液中受影响的红细胞。因此，肝豆状核变性患者的血浆ASM水平升高，神经酰胺和磷脂酰丝氨酸阳性红细胞呈结构性增加。我们的数据提示肝硬变和肝豆状核变性贫血的一种以前未知的机制。
Wilson disease is caused by accumulation of Cu2+ in cells, which results in liver cirrhosis and, occasionally, anemia. Here, we show that Cu2+ triggers hepatocyte apoptosis through activation of acid sphingomyelinase (Asm) and release of ceramide. Genetic deficiency or pharmacological inhibition of Asm prevented Cu2+-induced hepatocyte apoptosis and protected rats, genetically prone to develop Wilson disease, from acute hepatocyte death, liver failure and early death. Cu2+ induced the secretion of activated Asm from leukocytes, leading to ceramide release in and phosphatidylserine exposure on erythrocytes, events also prevented by inhibition of Asm. Phosphatidylserine exposure resulted in immediate clearance of affected erythrocytes from the blood in mice. Accordingly, individuals with Wilson disease showed elevated plasma levels of Asm, and displayed a constitutive increase of ceramide- and phosphatidylserine-positive erythrocytes. Our data suggest a previously unidentified mechanism for liver cirrhosis and anemia in Wilson disease.