ATP citrate lyase is an important component of cell growth and transformation
ATP citrate lyase is an important component of cell growth and transformation
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DOI：
10.1038/sj.onc.1208773
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发表时间：
2005-09-01
期刊：
影响因子：
8
通讯作者：
Thompson, CB
中科院分区：
文献类型：
--
作者：
Bauer, DE;Hatzivassiliou, G;Thompson, CB
细胞增殖需要持续的脂质和脂质前体的供应，以支持膜生物发生和蛋白质莫迪。阳离子。细胞因子对造血细胞的刺激直接刺激超过生物能量需求的葡萄糖利用，导致从氧化代谢向糖酵解代谢的转变。这种代谢形式的一个潜在好处是将葡萄糖引导到生物合成途径中。在这里，我们报告了葡萄糖以一种受细胞因子可获得性和PI3K/Akt信号通路调节的方式支持正在生长的造血细胞中的从头合成脂质。葡萄糖到脂质的净转化依赖于细胞通过三磷酸腺苷柠檬酸裂解酶(ACL)的作用从线粒体衍生的柠檬酸产生胞浆乙酰辅酶A的能力。稳定的ACL基因敲除会导致葡萄糖依赖的脂质合成的显著障碍和线粒体膜电位的升高。ACL基因敲除的细胞表现为细胞因子刺激的细胞增殖减少。相反，这些细胞抵抗细胞因子或葡萄糖退出所导致的细胞死亡。然而，ACL基因敲除显著削弱了Akt介导的体内肿瘤发生。这些数据表明，参与葡萄糖到脂肪转化的酶可能是治疗病理性细胞生长的靶点。
Cell proliferation requires a constant supply of lipids and lipid precursors to fuel membrane biogenesis and protein modi. cation. Cytokine stimulation of hematopoietic cells directly stimulates glucose utilization in excess of bioenergetic demand, resulting in a shift from oxidative to glycolytic metabolism. A potential benefit of this form of metabolism is the channeling of glucose into biosynthetic pathways. Here we report that glucose supports de novo lipid synthesis in growing hematopoietic cells in a manner regulated by cytokine availability and the PI3K/Akt signaling pathway. The net conversion of glucose to lipid is dependent on the ability of cells to produce cytosolic acetyl CoA from mitochondria-derived citrate through the action of ATP citrate lyase (ACL). Stable knockdown of ACL leads to a significant impairment of glucose-dependent lipid synthesis and an elevation of mitochondrial membrane potential. Cells with ACL knockdown display decreased cytokine-stimulated cell proliferation. In contrast, these cells resist cell death induced by either cytokine or glucose withdrawal. However, ACL knockdown significantly impairs Akt-mediated tumorigenesis in vivo. These data suggest that enzymes involved in the conversion of glucose to lipid may be targets for the treatment of pathologic cell growth.