Metabolic flexibility is the capacity of cells to alter fuel metabolism in response to changes in metabolic demand or nutrient availability. It is critical for maintaining cellular bioenergetics and is involved in the pathogenesis of cardiovascular disease and metabolic disorders. However, the regulation and function of metabolic flexibility in lymphatic endothelial cells (LECs) remain unclear. We have previously shown that glycolysis is the predominant metabolic pathway to generate ATP in LECs and that fibroblast growth factor receptor (FGFR) signaling controls lymphatic vessel formation by promoting glycolysis. Here, we found that chemical inhibition of FGFR activity or knockdown of FGFR1 induces substantial upregulation of fatty acid β-oxidation (FAO) while reducing glycolysis and cellular ATP generation in LECs. Interestingly, such compensatory elevation was not observed in glucose oxidation and glutamine oxidation. Mechanistic studies show that FGFR blockade promotes the expression of carnitine palmitoyltransferase 1A (CPT1A), a rate-limiting enzyme of FAO; this is achieved by dampened extracellular signal-regulated protein kinase activation, which in turn upregulates the expression of the peroxisome proliferator-activated receptor alpha. Metabolic analysis further demonstrates that CPT1A depletion decreases total cellular ATP levels in FGFR1-deficient rather than wildtype LECs. This result suggests that FAO, which makes a negligible contribution to cellular energy under normal conditions, can partially compensate for energy deficiency caused by FGFR inhibition. Consequently, CPT1A silencing potentiates the effect of FGFR1 knockdown on impeding LEC proliferation and migration. Collectively, our study identified a key role of metabolic flexibility in modulating the effect of FGFR signaling on LEC growth.

中文翻译：

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代谢灵活性维持 FGFR 信号缺陷淋巴管内皮细胞的增殖和迁移。

代谢灵活性是细胞根据代谢需求或营养供应的变化改变燃料代谢的能力。它对于维持细胞生物能量学至关重要，并且参与心血管疾病和代谢紊乱的发病机制。然而，淋巴管内皮细胞 (LEC) 代谢灵活性的调节和功能仍不清楚。我们之前已经表明，糖酵解是 LEC 中产生 ATP 的主要代谢途径，并且成纤维细胞生长因子受体 (FGFR) 信号通过促进糖酵解来控制淋巴管的形成。在这里，我们发现 FGFR 活性的化学抑制或 FGFR1 的敲低诱导脂肪酸 β-氧化 (FAO) 的显着上调，同时减少 LEC 中的糖酵解和细胞 ATP 生成。有趣的是，在葡萄糖氧化和谷氨酰胺氧化中没有观察到这种补偿性升高。机理研究表明，FGFR 阻断促进肉碱棕榈酰转移酶 1A (CPT1A) 的表达，这是一种粮农组织的限速酶；这是通过抑制细胞外信号调节的蛋白激酶激活来实现的，这反过来又上调了过氧化物酶体增殖物激活受体 α 的表达。代谢分析进一步表明，在 FGFR1 缺陷型而非野生型 LEC 中，CPT1A 耗竭会降低细胞总 ATP 水平。这一结果表明，FAO 在正常条件下对细胞能量的贡献可以忽略不计，但可以部分补偿由 FGFR 抑制引起的能量不足。最后，CPT1A 沉默增强了 FGFR1 敲低对阻碍 LEC 增殖和迁移的影响。总的来说，我们的研究确定了代谢灵活性在调节 FGFR 信号对 LEC 生长的影响方面的关键作用。