瑞士苏黎世联邦理工学院Christian Wolfrum小组发现，葡萄糖通过高尔基体PtdIns4P介导的ATGL调节来控制脂肪分解。2024年4月1日，《自然—细胞生物学》杂志在线发表了这项成果。

主要营养素葡萄糖、氨基酸和脂肪酸（FA）之间的代谢相互影响确保了全身代谢平衡。葡萄糖和脂肪酸的供应协调以满足各种生理需求尤为重要，因为营养水平失调会导致代谢紊乱，如糖尿病和代谢功能障碍相关性脂肪性肝炎（MASH）。针对血糖水平的波动，脂肪分解被认为主要是通过胰岛素、儿茶酚胺和胰高血糖素的激素调节来控制脂滴中FA的释放。然而，是否存在通过葡萄糖感应直接调节脂肪分解的一般细胞内在机制在很大程度上仍是未知数。

研究人员报告了这种内在机制的发现，它涉及高尔基体PtdIns4P通过细胞内葡萄糖感应介导的对脂肪甘油三酯脂肪酶（ATGL）驱动的脂肪分解的调节。从机理上讲，细胞内葡萄糖耗竭会导致高尔基体PtdIns4P水平降低，从而减少E3连接酶复合物CUL7^FBXW8在高尔基体内的组装。E3连接酶复合物水平的降低导致ATGL在高尔基体中的多泛素化减少，ATGL驱动的脂肪分解增强。

这种细胞内在机制可调节细胞内脂肪酸池及其细胞外释放，以满足空腹和葡萄糖剥夺时的生理需求。此外，在单纯性肝脂肪变性和MASH的小鼠模型中，以及在人脂肪肝移植物的体外灌注过程中，对高尔基体PtdIns4P-CUL7^FBXW8-ATGL轴的遗传和药物操作可导致脂肪变性的改善，这表明该通路可能是代谢功能障碍相关脂肪性肝病和MASH的一个潜在靶点。

附：英文原文

Title: Glucose controls lipolysis through Golgi PtdIns4P-mediated regulation of ATGL

Author: Ding, Lianggong, Huwyler, Florian, Long, Fen, Yang, Wu, Binz, Jonas, Wernl, Kendra, Pfister, Matthias, Klug, Manuel, Balaz, Miroslav, Ukropcova, Barbara, Ukropec, Jozef, Wu, Chunyan, Wang, Tongtong, Gao, Min, Clavien, Pierre-Alain, Dutkowski, Philipp, Tibbitt, Mark W., Wolfrum, Christian

Issue&Volume: 2024-04-01

Abstract: 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 CUL7FBXW8 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–CUL7FBXW8–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.

DOI: 10.1038/s41556-024-01386-y

Source: https://www.nature.com/articles/s41556-024-01386-y