Metabolic crosstalk of the major nutrients glucose, amino acids and fatty acids (FAs) ensures systemic metabolic homeostasis. The coordination between the supply of glucose and FAs to meet various physiological demands is especially important as improper nutrient levels lead to metabolic disorders, such as diabetes and metabolic dysfunction-associated steatohepatitis (MASH). In response to the oscillations in blood glucose levels, lipolysis is thought to be mainly regulated hormonally to control FA liberation from lipid droplets by insulin, catecholamine and glucagon. However, whether general cell-intrinsic mechanisms exist to directly modulate lipolysis via glucose sensing remains largely unknown. Here we report the identification of such an intrinsic mechanism, which involves Golgi PtdIns4P-mediated regulation of adipose triglyceride lipase (ATGL)-driven lipolysis via intracellular glucose sensing. Mechanistically, depletion of intracellular glucose results in lower Golgi PtdIns4P levels, and thus reduced assembly of the E3 ligase complex CUL7^FBXW8 in the Golgi apparatus. Decreased levels of the E3 ligase complex lead to reduced polyubiquitylation of ATGL in the Golgi and enhancement of ATGL-driven lipolysis. This cell-intrinsic mechanism regulates both the pool of intracellular FAs and their extracellular release to meet physiological demands during fasting and glucose deprivation. Moreover, genetic and pharmacological manipulation of the Golgi PtdIns4P–CUL7^FBXW8–ATGL axis in mouse models of simple hepatic steatosis and MASH, as well as during ex vivo perfusion of a human steatotic liver graft leads to the amelioration of steatosis, suggesting that this pathway might be a promising target for metabolic dysfunction-associated steatotic liver disease and possibly MASH.

主要营养素葡萄糖、氨基酸和脂肪酸 (FA) 的代谢串扰确保了全身代谢稳态。协调葡萄糖和脂肪酸的供应以满足各种生理需求尤为重要，因为营养水平不当会导致代谢紊乱，例如糖尿病和代谢功能障碍相关的脂肪性肝炎 (MASH)。为了响应血糖水平的波动，脂肪分解被认为主要通过激素调节来控制胰岛素、儿茶酚胺和胰高血糖素从脂滴中释放 FA。然而，是否存在通过葡萄糖传感直接调节脂肪分解的一般细胞内在机制仍然很大程度上未知。在这里，我们报告了这种内在机制的识别，该机制涉及高尔基体 PtdIns4P 介导的通过细胞内葡萄糖传感对脂肪甘油三酯脂肪酶 (ATGL) 驱动的脂肪分解的调节。从机制上讲，细胞内葡萄糖的消耗会导致高尔基体 PtdIns4P 水平降低，从而减少高尔基体中E3 连接酶复合物 CUL7 ^FBXW8的组装。 E3 连接酶复合物水平的降低导致高尔基体中 ATGL 多泛素化的减少和 ATGL 驱动的脂肪分解的增强。这种细胞内在机制调节细胞内 FA 库及其细胞外释放，以满足禁食和葡萄糖剥夺期间的生理需求。此外，在单纯性肝脂肪变性和 MASH 小鼠模型中，以及在人脂肪变性肝移植物的离体灌注过程中，对高尔基体 PtdIns4P–CUL7 ^FBXW8 –ATGL 轴进行遗传和药理学操作，可改善脂肪变性，这表明该途径可能是代谢功能障碍相关脂肪肝病和 MASH 的一个有希望的靶点。