Tuberous Sclerosis Complex 2 Loss Increases Lysophosphatidylcholine Synthesis in Lymphangioleiomyomatosis
Tuberous Sclerosis Complex 2 Loss Increases Lysophosphatidylcholine Synthesis in Lymphangioleiomyomatosis
复制标题
DOI：
10.1165/rcmb.2014-0379rc
复制
发表时间：
2015-07-01
影响因子：
6.4
通讯作者：
Henske, Elizabeth P.
中科院分区：
文献类型：
--
作者：
Priolo, Carmen;Ricoult, Stephane J. H.;Henske, Elizabeth P.
淋巴管平滑肌瘤病 (LAM) 是一种影响女性的破坏性肺部疾病。 LAM 是由结节性硬化症 (TSC) 基因突变引起的。 TSC 蛋白复合物抑制雷帕霉素复合物 1 (mTORC1) 的机械/哺乳动物靶标，雷帕霉素复合物是细胞代谢的主要调节因子。使用基于质谱的脂质分析，我们分析了 LAM 患者的血浆，发现与健康对照女性相比，四种溶血磷脂酰胆碱 (LPC)（C16:0、C18:0、C18:1 和 C20:4）的水平升高。为了研究这些脂质是否以 TSC2 依赖性方式产生，我们分析了 TSC/LAM 的体外临床前模型，发现相对于表达 TSC2 的对照细胞，TSC2 缺陷细胞中 LPC 明显积累。这些溶甘油磷脂的变化与其他磷脂和中性脂质种类的变化同时发生。在 TSC2 缺陷细胞中，用雷帕霉素或 torin1 治疗或下调甾醇调节元件结合蛋白 (SREBP)（一种脂肪生成转录因子）并不能抑制 LPC。抑制磷脂酶 A2 的不同亚型可降低 TSC2 缺陷细胞的增殖。总的来说，这些结果表明，TSC2 缺陷细胞增强了胆碱磷脂代谢，并揭示了 TSC 蛋白在胆碱溶甘油磷脂代谢中的新功能，对疾病发病机制和靶向治疗策略具有影响。
Lymphangioleiomyomatosis (LAM) is a destructive lung disease affecting women. LAM is caused by mutations in the tuberous sclerosis complex (TSC) genes. The TSC protein complex inhibits the mechanistic/mammalian target of rapamycin complex 1 (mTORC1), which is a master regulator of cellular metabolism. Using mass spectrometry-based lipid profiling, we analyzed plasma from patients with LAM and discovered elevated levels of four lysophosphatidylcholine (LPC) species (C16: 0, C18: 0, C18: 1, and C20: 4) compared with those in healthy control women. To investigate whether these lipids are generated in a TSC2-dependent manner, we profiled in vitro preclinical models of TSC/LAM and found significant LPC accumulation in TSC2-deficient cells relative to TSC2-expressing control cells. These lysoglycerophospholipid changes occurred alongside changes in other phospholipid and neutral lipid species. Treatment with rapamycin or torin1 or downregulation of sterol regulatory element-binding protein (SREBP), a lipogenic transcription factor, did not suppress LPC in TSC2-deficient cells. Inhibition of distinct isoforms of phospholipase A2 decreased the proliferation of TSC2-deficient cells. Collectively, these results demonstrate that TSC2-deficient cells have enhanced choline phospholipid metabolism and reveal a novel function of the TSC proteins in choline lysoglycerophospholipid metabolism, with implications for disease pathogenesis and targeted therapeutic strategies.