糖原代谢中糖噬的作用及调控机制

Role and regulatory mechanism of glycophagy in glycogen metabolism

背景:糖噬是选择性自噬的一种,在糖原的降解过程中有特有的作用,但对其调控的机制仍然了解有限。目的:从糖噬底物的形态、功能、降解途径分析,进而对糖噬的作用和调控信号通路进行综述,阐明糖原代谢中糖噬的作用及调控机制。方法:通过关键词glycophagy [Topic]、Glycogen [Title] AND autophagy [Title]、Glycogen-storage-disease [Title]、Lafora-disease [Title]、pompedisease[Title]、Von-Gierke-disease[Title]在Web of Science、PubMed、EBSCO数据库中检索相关英文文献,并通过糖噬[Topic]、糖原自噬[Title]、糖原累积[Title]、糖原贮积[Title]在CNKI数据库中检索相关中文文献,以及手动补充相关文献。阅读标题和摘要进行初选,最终根据排除标准整理出87篇文献进行综述。结果与结论:糖噬与糖原的氧化磷酸化途径共同构成了体内糖原的降解系统,有为糖脂和脂肪的生成提供底物,以及在能量应激期间糖噬体内贮存一定量的糖原预防更严重事件发生的积极作用,但糖噬障碍会引起拉福拉病、方基盖氏病、庞贝病等疾病,甚至威胁生命。通过激活PI3K/mTOR、Akt/FoxO、SGK1/mTOR 3条信号通路可以起到抑制糖噬的作用;通过激活cAMP/PKA、G6PC/SIRT1/FoxO、Ca^(2+)、cGMP/PKG/GSK-3β4条信号通路可以起到激活糖噬的作用。但仍存在诸多问题亟待解决:①糖噬调节有无性别间差异;②什么信号或刺激导致了糖噬过程中糖原贮存增加;③何种物质触发溶酶体中的酶开始降解糖原;④糖噬过程糖原降解和贮存有无平衡点;⑤糖噬各个调节通路间怎么协调配合,其作用机制及药理学机制是什么。

BACKGROUND:Glycophagy is a selective autophagy,which plays a unique role in glycogen degradation,but the mechanism of its regulation is still limited.OBJECTIVE:To review the function and regulatory signaling pathway of glycophagy based on the morphology,function and degradation pathway of glycophagy substrate,and then to clarify the role and regulatory mechanism of glycophagy in glycogen metabolism.METHODS:Web of Science,PubMed,and EBSCO databases were searched for the relevant English literatures using the search terms of glycophagy[Topic],Glycogen[Title]AND autophagy[Title],Glycogen-storage-disease[Title],Lafora-disease[Title],pompe-disease[Title],and Von-Gierke-disease[Title].CNKI database was also searched to retrieve the relevant Chinese literatures with the search terms of glycogenated[Topic],glycogen autophagy[Title],glycogen accumulation[Title],and glycogen storage[Title].Relevant literature was also manually retrieved.Based on the exclusion criteria,87 papers were included for final review by reading the title and abstract.RESULTS AND CONCLUSION:The glycogen degradation system in vivo consists of glycophagy and glycogen oxidative phosphorylation,which can provide substrates for the generation of glycolipids and fats,and prevent more serious events through storing a certain amount of glycogen in glycogenosomes during energy stress.However,glycophagy disorders can cause some diseases that are even life-threatening,such as Lafora disease,von Gierke disease and Pompe disease.The activation of PI3K/mTOR,Akt/FoxO and SGK1/mTOR signaling pathways could inhibit glycophagy,while glycophagy can be elicited through the activation of cAMP/PKA,G6PC/SIRT1/FoxO,Ca^(2+),cGMP/PKG/GSK-3βsignaling pathways.However,There are many problems that need to be solved,such as:(1)whether there is sex difference during glycophagy;(2)what signals or stimuli lead to an increase in glycogen storage during glycophagy;(3)what substances trigger enzymes in lysosomes to degrade glycogen;(4)whether there is a balance point between glycogen degradation and storage during glycophagy;and(5)how the various regulatory pathways of glycophagy are coordinated,and what are the mechanisms of action and pharmacology.