ABHD5 is an essential coactivator of ATGL, the rate-limiting triglyceride (TG) lipase in many cell types. Importantly, ABHD5 also functions as a tumor suppressor, and ABHD5 mRNA expression levels correlate with patient survival for several cancers. Nevertheless, the mechanisms involved in ABHD5-dependent tumor suppression are not known. We found that overexpression of ABHD5 induces cell-cycle arrest at the G1 phase and causes growth retardation in a panel of prostate cancer cells. Transcriptomic profiling and biochemical analysis revealed that genetic or pharmacological activation of lipolysis by ABHD5 potently inhibits mTORC1 signaling, leading to a significant downregulation of protein synthesis. Mechanistically, we found that ABHD5 elevates intracellular AMP content, which activates AMPK, leading to inhibition of mTORC1. Interestingly, ABHD5-dependent suppression of mTORC1 was abrogated by pharmacological inhibition of DGAT1 or DGAT2, isoenzymes that re-esterify fatty acids in a process that consumes ATP. Collectively, this study maps out a novel molecular pathway crucial for limiting cancer cell proliferation, in which ABHD5-mediated lipolysis creates an energy-consuming futile cycle between TG hydrolysis and resynthesis, leading to inhibition of mTORC1 and cancer cell growth arrest.

中文翻译：

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ABHD5 通过 AMPK/mTORC1 通路的脂解依赖性激活来抑制癌细胞合成代谢

ABHD5 是 ATGL 的重要共激活剂，ATGL 是许多细胞类型中的限速甘油三酯 (TG) 脂肪酶。重要的是，ABHD5 还具有肿瘤抑制因子的功能，并且 ABHD5 mRNA 表达水平与多种癌症患者的生存率相关。然而，ABHD5 依赖性肿瘤抑制的机制尚不清楚。我们发现 ABHD5 的过度表达会诱导细胞周期停滞在 G1 期，并导致一组前列腺癌细胞生长迟缓。转录组分析和生化分析表明，ABHD5 对脂肪分解的遗传或药理学激活可有效抑制 mTORC1 信号传导，从而导致蛋白质合成显着下调。从机制上讲，我们发现 ABHD5 提高细胞内 AMP 含量，从而激活 AMPK，从而抑制 mTORC1。有趣的是，ABHD5 依赖性 mTORC1 抑制可通过 DGAT1 或 DGAT2 的药理学抑制来消除，DGAT1 或 DGAT2 是在消耗 ATP 的过程中重新酯化脂肪酸的同工酶。总的来说，这项研究描绘了一条对于限制癌细胞增殖至关重要的新分子途径，其中 ABHD5 介导的脂肪分解在 TG 水解和再合成之间创建了一个消耗能量的无效循环，从而导致 mTORC1 的抑制和癌细胞生长停滞。