Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
Nat Metab. 2022 Dec;4(12):1792-1811. doi: 10.1038/s42255-022-00706-6. Epub 2022 Dec 19.
The mechanistic target of rapamycin complex 1 (mTORC1) senses and relays environmental signals from growth factors and nutrients to metabolic networks and adaptive cellular systems to control the synthesis and breakdown of macromolecules; however, beyond inducing de novo lipid synthesis, the role of mTORC1 in controlling cellular lipid content remains poorly understood. Here we show that inhibition of mTORC1 via small molecule inhibitors or nutrient deprivation leads to the accumulation of intracellular triglycerides in both cultured cells and a mouse tumor model. The elevated triglyceride pool following mTORC1 inhibition stems from the lysosome-dependent, but autophagy-independent, hydrolysis of phospholipid fatty acids. The liberated fatty acids are available for either triglyceride synthesis or β-oxidation. Distinct from the established role of mTORC1 activation in promoting de novo lipid synthesis, our data indicate that mTORC1 inhibition triggers membrane phospholipid trafficking to the lysosome for catabolism and an adaptive shift in the use of constituent fatty acids for storage or energy production.
雷帕霉素靶蛋白复合体 1（mTORC1）作为一种机械靶点，能够感知和传递生长因子和营养物质等环境信号，并将其传递给代谢网络和适应性细胞系统，从而控制大分子的合成和分解；然而，除了诱导从头合成脂质之外，mTORC1 控制细胞脂质含量的作用仍知之甚少。本研究表明，通过小分子抑制剂或营养剥夺抑制 mTORC1 会导致培养细胞和小鼠肿瘤模型中细胞内甘油三酯的积累。mTORC1 抑制后甘油三酯池的增加源于溶酶体依赖性、但自噬非依赖性的磷脂脂肪酸水解。释放的脂肪酸可用于甘油三酯合成或β-氧化。与 mTORC1 激活促进从头合成脂质的既定作用不同，我们的数据表明，mTORC1 抑制会触发膜磷脂向溶酶体的转运进行分解代谢，并导致组成脂肪酸的利用发生适应性转变，用于储存或能量产生。
