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内质网应激响应在脂肪组织中的代谢调节作用

胡雨荣, 陈勇, 刘勇^*

湖北省细胞稳态重点实验室，武汉大学生命科学学院，武汉 430072

摘要

在真核细胞中，内质网是蛋白合成、加工及质量监控的关键细胞器，也是Ca2+储存及脂质合成的重要场所。细胞通过未折叠蛋白响应(unfolded protein response, UPR)感应外界不同刺激引发的内质网应激，在维持细胞功能稳态中发挥至关重要的作用。在哺乳动物中，三个位于内质网的跨膜蛋白——肌醇依赖酶1α (inositol-requiring enzyme 1α, IRE1α)、PKR样内质网激酶(PKR-like endoplasmic reticulum kinase, PERK)和活化转录因子6 (activating transcription factor 6, ATF6)能够感应内质网腔内未折叠蛋白或错误折叠蛋白的积累，协同介导三条经典的UPR信号通路，通过促进下游靶基因的表达恢复内质网的蛋白折叠能力。近期大量研究表明，UPR参与细胞代谢与能量平衡的精细调节过程。脂肪组织是机体能量储存与消耗的关键场所，通过分泌多种脂肪因子调节机体的能量平衡和糖脂代谢；而在营养过剩状态下，多种内在因素和外部环境相互作用导致脂肪组织发生代谢炎症和功能异常，尤其是脂肪组织中的内质网应激响应与脂肪组织的功能紊乱密切相关，在肥胖和2型糖尿病等代谢疾病的发生和发展中发挥重要的作用。本综述旨在总结近年来有关UPR通路调节脂肪组织功能稳态方面的重要进展，探讨内质网应激响应与脂肪组织代谢紊乱的机制关联，以期促进我们深入了解肥胖及其相关代谢疾病的病理生理学基础。

关键词： 内质网应激; 未折叠蛋白响应; 脂肪组织; 代谢炎症; 肥胖

分类号：Q493.5

Role of endoplasmic reticulum stress response in regulation of adipose tissue metabolism

HU Yu-Rong, CHEN Yong, LIU Yong^*

Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China

Abstract

In eukaryotic cells, the endoplasmic reticulum (ER) is the key quality control organelle for cellular protein synthesis and processing. It also serves as an important site for Ca2+ storage and lipid biosynthesis. In response to a variety of external stimuli, a cellular unfolded protein response (UPR) is activated to handle ER stress caused by increased accumulation of unfolded or misfolded proteins at the ER. The UPR plays a crucial role in maintaining ER homeostasis and cell functions. Three ER-localized transmembrane proteins, inositol-requiring enzyme 1α (IRE1α), PKR-like ER kinase (PERK), and activating transcription factor 6 (ATF6), act to sense ER stress and mediate three canonical UPR signaling pathways. Besides restoring the protein folding capability to relieve ER stress, the UPR pathways have also been implicated in the regulation of cell metabolism and energy balance. In the state of overnutrition, ER stress has been documented to occur in adipose tissue that has a key role in energy storage and consumption. As an endocrine organ, adipose tissue regulates glucose and lipid metabolism through secreting adipocyte cytokines, and it undergoes metabolic inflammation during pathogenic development of obesity, insulin resistance and type 2 diabetes. In this review, we attempt to summarize the recent progress with regard to the UPR regulation of adipose tissue physiology. We wish to focus upon the mechanism by which ER stress response is linked to adipose tissue dysfunction, hoping to promote our current understanding of UPR signaling in the pathophysiology of obesity and related metabolic diseases.

Key words: endoplasmic reticulum stress; unfolded protein response; adipose tissue; metabolic inflammation; obesity

收稿日期：2020-04-06　　录用日期：2020-05-13

通讯作者：刘勇　　E-mail: liuyong31279@whu.edu.cn

DOI: 10.13294/j.aps.2021.0005

引用本文：

胡雨荣, 陈勇, 刘勇. 内质网应激响应在脂肪组织中的代谢调节作用[J]. 生理学报 2021; 73 (1): 115-125.

HU Yu-Rong, CHEN Yong, LIU Yong. Role of endoplasmic reticulum stress response in regulation of adipose tissue metabolism. Acta Physiol Sin 2021; 73 (1): 115-125 (in Chinese with English abstract).