Endoplasmic Reticulum Stress and Metabolic Syndrome: Mechanisms and Therapeutic Potential /内质网应激与代谢综合征的机制及治疗潜能

代谢综合征是指包括肥胖、脂质代谢紊乱、高血压和胰岛素抵抗在内的代谢异常症候群,是心血管和神经系统疾病的独立危险因素,发病过程中伴有脂肪因子（细胞因子和趋化因子）和瘦素的分泌失调。这些改变调节免疫、炎症反应,引起下丘脑饱食中枢的失衡。代谢综合征和神经系统疾病（如中风、抑郁症、阿兹海默病）存在相关性的分子机制目前尚不清楚。目前已知的联系代谢综合征和心血管疾病、神经疾病的分子和细胞机制包括：氧应激、糖、脂代谢的改变,胰岛素、瘦素分泌异常,凋亡和自噬等。最新研究表明,内质网应激反应（或未折叠蛋白反应）在代谢综合征患者的各个组织中被激活。下丘脑的内质网应激与炎症和瘦素、胰岛素抵抗有关。肝脏的内质网应激导致脂质沉积和胰岛素抵抗,而脂肪组织中的内质网应激触发炎症反应,调节脂肪因子的分泌。同时炎症反应可以进一步恶化内质网应激。另外,内质网应激直接导致自噬的发生而自噬可进一步加剧内质网应激。这些内质网应激与细胞损伤机制的相互作用可以影响胰岛素信号转导从而参与代谢综合征的发病。本文不仅综述了近期关于代谢综合征引起的心血管和神经系统疾病的发病机制,也分析了内质网应激在代谢综合征所致心血管和神经系统疾病中的作用。

Endoplasmic Reticulum Stress and Metabolic Syndrome: Mechanisms and Therapeutic Potential

The nomenclature "metabolic syndrome" refers to a cluster of disorders including obesity, dyslipidemia, hypertension, and insulin resistance. It is a primary risk factor for cardiovascular and neurological diseases accompanied by dysregulated adipokines (cytokines and chemokines) and leptin, a peptide hormone secreted by white adipose tissue. These changes modulate immune and inflammatory responses, prompting the reset of the hypothalamic “body weight/appetite/satiety set point”. The precise tie between metabolic syndrome and neurological disorders such as stroke, depression and Alzheimer's disease remains largely elusive. A number of cellular and molecular mechanisms have been put forward for the metabolic syndrome-associated cardiovascular and neurological anomalies including oxidative stress, alteration in glucose and lipid metabolism, abnormal insulin and leptin signaling, apoptosis, and autophagy. More recent evidence depicted that endoplasmic reticulum (ER) stress, also known as unfolded protein response (UPR), gets activated in the context of metabolic syndrome. Hypothalamic ER stress leads to inflammation and resistance to leptin/insulin signaling. Hepatic ER stress promotes the onset and development of insulin resistance while ER stress in adipose tissues facilitates inflammation to cause secretion of adipokines. To the contrary, inflammation aggravates ER stress. ER stress activates autophagy while autophagy induction may, in turn, enhance ER stress. These interplays between ER stress and cell injurious machinery compromise insulin signaling, thereby contributing to the onset and development of metabolic syndrome. This synthetic min-review of recent literature not only describes the involvement of cardiovascular and neurological systems in the pathogenesis of metabolic syndrome, but also dissects the role of ER stress as well as its interplay with autophagy and inflammation in cardiovascular and neurological disorders in metabolic syndrome.