细胞内ATP水平调节机制在肥胖病理生理中的作用

Novel role of intracellular ATP in obesity pathology

ATP是细胞的重要能源。传统观点认为细胞内ATP水平相对恒定,不会出现持续升高。而新的研究提示:在能量过剩状态下,ATP水平在多种组织中持续升高,这种升高与能量过剩引起的代谢紊乱密切相关,但其升高机制尚不清楚。本文通过回顾本研究组前期实验结果和文献,论述调节细胞内ATP水平的多种因素,其中涉及超氧离子、线粒体炫、抗氧化剂、抗凋亡蛋白(Bcl-xL)、AMP活化的蛋白激酶以及二甲双胍等,重点讨论这些因素改变ATP设定点的作用及其潜在机制,评估它们在细胞内ATP水平升高或降低中扮演的角色。本文以能量过剩的分子机制为中心,探讨细胞内ATP水平升高导致胰岛素抵抗的分子机制,同时阐明新的实验结果与ATP传统观点之间发生矛盾的可能原因。作者认为在肥胖条件下,ATP水平升高是细胞能量过剩的重要信号,该信号通过激活反馈通路抑制线粒体功能,造成糖脂代谢紊乱。

ATP is an important energy source for cells. Traditionally, intracellular ATP levels are believed to be relatively stable and will not rise consistently in the physiological conditions. However, new studies suggest that ATP levels may rise in multiple tissues under the condition of energy surplus contributing to the metabolic disorders in obesity. However, the molecular mechanism of ATP elevation remains unknown in obesity except the increase in energy supply. Based on our experimental results and the findings reported in the literature, we discuss the cellular and molecular mechanisms by which ATP levels are regulated in cells by multiple factors, including superoxide ions, mitochondrial flash, antioxidants, anti-apoptotic molecule Bcl-xL, AMP-activated protein kinase(AMPK) and metformin. Contribution of these factors to the alteration of ATP set-point will be discussed together with their impact on insulin resistance in type 2 diabetes mellitus. With a focus on the energy surplus in obesity, we explore the mechanism of insulin resistance induced by ATP elevation and provide an answer to the contradiction between the new experimental results and the traditional viewpoint of intracellular ATP. We propose that elevation of intracellular ATP may lead to metabolic disorder in obesity through activation of a feedback mechanism that inhibits mitochondrial function.