Ceramide accumulation is associated with increased apoptotic cell death in cultured fibroblasts of sphingolipid activator protein-deficient mouse but not in fibroblasts of patients with Farber disease
Ceramide accumulation is associated with increased apoptotic cell death in cultured fibroblasts of sphingolipid activator protein-deficient mouse but not in fibroblasts of patients with Farber disease
复制标题
DOI：
10.1023/a:1005590316064
复制
发表时间：
1999-06-01
影响因子：
4.2
通讯作者：
Suzuki, K
中科院分区：
文献类型：
--
作者：
Tohyama, J;Oya, Y;Suzuki, K
神经酰胺被认为是细胞生长、分化和凋亡的细胞内介质。已知肿瘤坏死因子、抗Fas抗体、放射和抗癌药物如放线菌素D通过激活鞘磷脂酶途径或神经酰胺合成酶产生神经酰胺而诱导几种细胞类型的凋亡。在这项研究中，我们研究了法伯病患者和鞘脂激活蛋白缺陷（sap -/-）小鼠成纤维细胞凋亡的发生。这些细胞积累神经酰胺作为结果的遗传缺陷的酸性神经酰胺酶和神经酰胺酶激活剂（sap-D），分别。法伯患者成纤维细胞和sap -/-小鼠成纤维细胞中神经酰胺的含量分别比对照组增加2.9倍和2.8倍。尽管神经酰胺积累程度相似，但仅在sap -/-小鼠的成纤维细胞中表现出凋亡特征的细胞增加，而法伯患者的成纤维细胞则没有。Farber成纤维细胞的胸苷摄取是正常的，而sap -/-小鼠成纤维细胞的胸苷摄取是正常的两倍，这与这两种细胞系中明显正常的生长和不同的凋亡细胞死亡率一致。这些数据表明，由于酸性神经酰胺酶或其激活剂缺陷的神经酰胺的溶酶体内积累可能不会发挥重要的作用，作为一个介导的细胞凋亡。sap -/-小鼠培养的成纤维细胞中细胞凋亡的增加可能是由神经酰胺积累以外的机制引起的。虽然比正常更频繁，但在体内sap -/-小鼠脑中未观察到显著的凋亡性细胞死亡。
Ceramide is recognized as an intracellular mediator of cell growth, differentiation and apoptosis. Tumour necrosis factor, anti-fas antibody, radiation and anticancer drugs such as actinomycin D are known to induce apoptosis in several cell types through generation of ceramide by activation of the sphingomyelinase pathway or ceramide synthetase. In this study, we examined the occurrence of apoptosis in fibroblasts from patients with Farber disease and from sphingolipid activator protein-deficient (sap -/-) mouse. These cells accumulate ceramide as the result of genetic deficiency of acid ceramidase and the ceramidase activator (sap-D), respectively. Amounts of ceramide in fibroblasts from Farber patients and in fibroblasts from sap -/- mouse were increased 2.9-fold and 2.8-fold, respectively, over the level of controls. Despite the similar degree of ceramide accumulation, cells exhibiting apoptotic features were increased only in fibroblasts from the sap -/- mouse but not those from the Farber patients. Thymidine uptake of Farber fibroblasts was normal while that of sap -/- mouse fibroblasts was twice normal, consistent with the apparently normal growth and the different rates of apoptotic cell death in these two cell lines. These data suggest that intralysosomal accumulation of ceramide due to defective acid ceramidase or its activator may not play an important role as a mediator of apoptosis. The increased apoptosis in the cultured fibroblasts from the sap -/- mouse may be caused by mechanisms other than the ceramide accumulation. Although more frequent than normal, significant apoptotic cell death was not observed in sap -/- mouse brain in vivo.