CDP-Diacylglycerol Synthetase Coordinates Cell Growth and Fat Storage through Phosphatidylinositol Metabolism and the Insulin Pathway

During development, animals usually undergo a rapid growth phase followed by a homeostatic stage when growth has ceased. The increase in cell size and number during the growth phase requires a large amount of lipids; while in the static state, excess lipids are usually stored in adipose tissues in preparation for nutrient-limited conditions. How cells coordinate growth and fat storage is not fully understood. Through a genetic screen we identified Drosophila melanogaster CDP-diacylglycerol synthetase (CDS/CdsA), which diverts phosphatidic acid from triacylglycerol synthesis to phosphatidylinositol (PI) synthesis and coordinates cell growth and fat storage. Loss of CdsA function causes significant accumulation of neutral lipids in many tissues along with reduced cell/organ size. These phenotypes can be traced back to reduced PI levels and, subsequently, low insulin pathway activity. Overexpressing CdsA rescues the fat storage and cell growth phenotypes of insulin pathway mutants, suggesting that CdsA coordinates cell/tissue growth and lipid storage through the insulin pathway. We also revealed that a DAG-to-PE route mediated by the choline/ethanolamine phosphotransferase Bbc may contribute to the growth of fat cells in CdsA RNAi.

在动物发育过程中，通常会先经历快速生长阶段，随后进入生长停滞的稳态阶段。生长阶段中细胞体积与数量的扩增需要消耗大量脂质；而在静态稳态阶段，过量脂质通常会储存在脂肪组织中，以备应对营养匮乏的环境。目前学界尚未完全阐明细胞如何协调生长与脂肪储存的机制。我们通过遗传筛选实验，鉴定出黑腹果蝇（Drosophila melanogaster）的CDP-二酰甘油合成酶（CDP-diacylglycerol synthetase，CDS/CdsA），该酶可将磷脂酸从三酰甘油合成通路分流至磷脂酰肌醇（phosphatidylinositol, PI）合成通路，从而实现细胞生长与脂肪储存的协调调控。CdsA功能缺失会导致多个组织内中性脂质显著积累，同时伴随细胞/器官体积缩小。上述表型可归因于PI水平降低，进而引发胰岛素通路活性下调。过表达CdsA能够挽救胰岛素通路突变体的脂肪储存与细胞生长异常表型，这表明CdsA可通过胰岛素通路协调细胞/组织的生长与脂质储存。我们还发现，由胆碱/乙醇胺磷酸转移酶Bbc介导的二酰甘油（diacylglycerol, DAG）向磷脂酰乙醇胺（phosphatidylethanolamine, PE）的转化通路，可能参与了CdsA RNA干扰（RNAi）条件下脂肪细胞的生长过程。