Aberrant fatty acid (FA) metabolism is a hallmark of proliferating cells, including untransformed fibroblasts or cancer cells. Lipolysis of intracellular triglyceride (TG) stores by adipose triglyceride lipase (ATGL) provides an important source of FAs serving as energy substrates, signaling molecules, and precursors for membrane lipids. To investigate if ATGL-mediated lipolysis impacts cell proliferation, we modified ATGL activity in murine embryonic fibroblasts (MEFs) and in five different cancer cell lines to determine the consequences on cell growth and metabolism. Genetic or pharmacological inhibition of ATGL in MEFs causes impaired FA oxidation, decreased ROS production, and a substrate switch from FA to glucose leading to decreased AMPK-mTOR signaling and higher cell proliferation rates. ATGL expression in these cancer cells is low when compared to MEFs. Additional ATGL knockdown in cancer cells did not significantly affect cellular lipid metabolism or cell proliferation whereas the ectopic overexpression of ATGL increased lipolysis and reduced proliferation. In contrast to ATGL silencing, pharmacological inhibition of ATGL by Atglistatin© impeded the proliferation of diverse cancer cell lines, which points at an ATGL-independent effect. Our data indicate a crucial role of ATGL-mediated lipolysis in the regulation of cell proliferation. The observed low ATGL activity in cancer cells may represent an evolutionary selection process and mechanism to sustain high cell proliferation rates. As the increasing ATGL activity decelerates proliferation of five different cancer cell lines this may represent a novel therapeutic strategy to counteract uncontrolled cell growth.

中文翻译：

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脂肪甘油三酯脂肪酶活性通过 AMP 激酶和 mTOR 信号传导调节癌细胞增殖。


脂肪酸（FA）代谢异常是增殖细胞（包括未转化的成纤维细胞或癌细胞）的标志。脂肪甘油三酯脂肪酶 (ATGL) 对细胞内甘油三酯 (TG) 储存的脂解提供了 FA 的重要来源，FA 充当能量底物、信号分子和膜脂的前体。为了研究 ATGL 介导的脂肪分解是否影响细胞增殖，我们修改了小鼠胚胎成纤维细胞 (MEF) 和五种不同癌细胞系中的 ATGL 活性，以确定对细胞生长和代谢的影响。 MEF 中 ATGL 的遗传或药理学抑制会导致 FA 氧化受损、ROS 产生减少以及底物从 FA 转换为葡萄糖，从而导致 AMPK-mTOR 信号传导减弱和细胞增殖率升高。与 MEF 相比，这些癌细胞中 ATGL 的表达较低。癌细胞中额外的 ATGL 敲低不会显着影响细胞脂质代谢或细胞增殖，而 ATGL 的异位过度表达会增加脂肪分解并减少增殖。与 ATGL 沉默相反，Atglistatin© 对 ATGL 的药理抑制阻碍了多种癌细胞系的增殖，这表明其效应不依赖于 ATGL。我们的数据表明 ATGL 介导的脂肪分解在细胞增殖调节中发挥着至关重要的作用。在癌细胞中观察到的低 ATGL 活性可能代表了维持高细胞增殖率的进化选择过程和机制。由于 ATGL 活性的增加会减缓五种不同癌细胞系的增殖，这可能代表了一种对抗不受控制的细胞生长的新治疗策略。