单磷酸腺苷激活的蛋白激酶(AMPK):能量、葡萄糖感受器和代谢性疾病治疗靶标
张宸崧*,王子涵,陈燕雯,万芷辰,王心茗,陈思薇,崔立枫

(厦门大学生命科学学院,细胞应激生物学国家重点实验室,福建 厦门 361102)

单磷酸腺苷激活的蛋白激酶(AMPK); 葡萄糖感受; 代谢稳态; 代谢疾病

Adenosine monophosphate-activated protein kinase(AMPK):an energy and glucose sensor and a therapeutic target in metabolic disease
ZHANG Chensong*,WANG Zihan,CHEN Yanwen,WAN Zhichen,WANG Xinming,CHEN Siwei,CUI Lifeng

(State Key Laboratory of Cellular Stress Biology,School of Life Sciences,Xiamen University,Xiamen 361102,China)

adenosine monophosphate-activated protein kinase(AMPK); glucose sensing; metabolic homeostasis; metabolic disease

DOI: 10.6043/j.issn.0438-0479.202111007

备注

代谢是一切生物体最基本的特征,单磷酸腺苷激活的蛋白激酶(AMPK)是机体内最重要的代谢调控蛋白之一.它在机体能量水平下降时被激活,通过磷酸化一系列下游因子促进分解代谢、抑制合成代谢,从而维持能量平衡.AMPK作为感知者和调节者,既能感受并维持代谢稳态,也能通过对代谢的“纠偏”缓解由代谢紊乱引起的糖尿病、脂肪肝等典型代谢性疾病症状; 而在更长时间尺度下调控AMPK,则可以延缓衰老、延长寿命.AMPK的这些功能和优势使其成为许多代谢疾病的重要靶标之一,并将有助于提升人类健康和生活质量.

Background: Metabolic processes represent an essential character of living organisms and are tightly regulated to meet the energy and nutrient demand of every cell, particularly under stress conditions. It has been found that the adenosine monophosphate activated protein kinase (AMPK) plays a critical role in metabolic processes. Once activated in low energy upon AMP or adenosine diphosphate (ADP) binding due to adenosine triphosphate (ATP) reduction, AMPK phosphorylates a variety of metabolic enzymes and regulators. Consequently, anabolic glucose, lipid and protein synthesis pathways are switched off to reduce ATP consumption, and catabolic activities are promoted to generate more ATP, thereby maintaining metabolic homeostasis. However, in metabolic disorders such as obesity, type II diabetes, cancer and aging, AMPK counters many cellular disturbances, including abnormal fat deposition, glucose intolerance, dysregulated growth and chronic inflammation, to restore whole-body abnormalities. Such roles confer AMPK a potential therapeutic target for metabolic diseases to improve human health and life quality.
Progress: Recent findings suggest an AMP- and ADP-independent mechanism through which AMPK is activated at low glucose level, which was previously considered as low energy. In low glucose in which AMPK is activated, e.g., in differentiated, mammalian cells starved for glucose or in liver tissues from fasted animals, no significant AMP or ADP elevation could be observed. In comparison, it is the decreased glycolytic intermediate fructose 1,6-bisphosphate (FBP) sensed by aldolase, which binds and converts FBP to phosphotrioses, that controls the activation of AMPK. When unoccupied by FBP at low glucose level, a portion of aldolase localized on the lysosome binds and in turn inhibits the calcium channel TRPV nearby. TRPV then interacts with vacuolar ATPase (v-ATPase) on the lysosomal surface, resulting in inhibition of the v-ATPase. The inhibited v-ATPase, together with its binding partner Ragulator, and then recruits AXIN scaffold along with liver kinase B1 (LKB1, the upstream kinase of AMPK) associated, to the surface of lysosome. This leads to AMPK phosphorylation and its activation on the lysosome. Such a non-canonical, lysosomal pathway shows two main characters distinct from the canonical, AMP- and ADP-dependent AMPK activation. First, the lysosomal pathway behaves in a spatial manner in which the lysosomal AMPK is specifically activated. In comparison, the AMP or ADP elevation happens under severer stress conditions (e.g., prolonged starvation and ischaemia) and causes allosteric changes in AMPK regardless of its localization, leading to activation of cytosolic and mitochondrial pools of AMPK in addition to the lysosomal pool. Second, the lysosomal pathway gives a relatively low level of AMPK activation, which can be further enhanced when bound to AMP or ADP. Therefore, the two mechanisms can operate independently but reinforce each other if both are active. Intriguingly, a larger activation of AMPK correlates with a wider spectrum of AMPK substrates to be phosphorylated.
Perspective: The introduction of lysosomal pathway fills the gaps of missing sensory mechanisms of AMPK for glucose. Therefore, AMPK could be regarded as a dual sensor: i) A genuine glucose (rather than ATP generated from glucose) sensor for nutrient surveillance even before any change (fall) in energy state has occurred, and activates AMPK in an AMP- and ADP-independent manner, thus protecting cells from potential energy stress. ii) An AMP or ADP sensor that monitors the decrease of energy levels. Such a hierarchical activation of AMPK and the accordingly adjusted regulations in metabolic processes guarantee that the metabolism can be fine-tuned when encountering different degrees of stress severity. Given that low glucose conditions can be observed in vivo in various physiological conditions such as the postabsorptive state and calorie restriction, and the calorie restriction shows strong effects in alleviating diabetic syndromes and retarding aging, components involved in the lysosomal pathway may be considered as potential targets for developing pharmacological agonists of AMPK. In particular, the immense efforts made over the past two decades for developing direct agonists for clinical use indicate that the high-level, long-term, or indiscriminate activation of AMPK, e.g., by pan-AMPK activators, often causes unexpected detrimental effects. A compartmentalized, lysosomally restricted AMPK activation may therefore offer an effective and safe way to treat metabolic diseases.