Biochemistry and Molecular Mechanism Laboratory, Agroprocessing and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology, Industrial Estate, Thiruvananthapuram, 695019, Kerala, India; Academy of Scientific & Innovative Research (AcSIR), New Delhi, India.
School of Health and Wellbeing/Functional Foods Research Group, University of Southern Queensland, Toowoomba, QLD, 4350, Australia.
Eur J Pharmacol. 2019 Oct 5;860:172553. doi: 10.1016/j.ejphar.2019.172553. Epub 2019 Jul 17.
Endoplasmic reticulum (ER) stress, a change in the ER homeostasis, leads to initiation of the unfolded protein response (UPR). The primary functions of the UPR are to restore the ER's physiological activity and coordinate the apoptotic and adaptive responses. Pathophysiological conditions that augment ER stress include hypoxia, misfolded and/or mutated protein accumulation, and high glucose. Prolonged ER stress is a critical factor in the pathogenesis of metabolic syndrome including type 2 diabetes mellitus, cardiovascular diseases, atherosclerosis, obesity, and fatty liver disease. UPR is a complex homeostatic pathway between newly synthesized proteins and their maturation, although the regulatory mechanisms contributing to the UPR and the possible therapeutic strategies are yet to be clarified. Therefore, a comprehensive understanding of the underlying molecular mechanisms is necessary to develop therapeutic interventions targeting ER stress response. In this review, we discuss the role of ER stress and UPR signaling in the pathogenesis of metabolic syndrome, highlighting the main functions of UPR components. We have emphasized the use of novel small molecular chemical chaperones, considered as modulators of ER stress. The initial studies with these chemical chaperones are promising, but detailed studies are required to define their efficacy and adverse effects during therapeutic use in humans.
内质网（ER）应激是内质网稳态的改变，导致未折叠蛋白反应（UPR）的启动。UPR 的主要功能是恢复 ER 的生理活性，并协调细胞凋亡和适应性反应。增加 ER 应激的病理生理条件包括缺氧、错误折叠和/或突变蛋白积累以及高血糖。长期 ER 应激是代谢综合征发病机制的一个关键因素，包括 2 型糖尿病、心血管疾病、动脉粥样硬化、肥胖和脂肪肝疾病。UPR 是新合成蛋白质与其成熟之间的复杂的稳态途径，尽管调节 UPR 的调控机制和可能的治疗策略尚不清楚。因此，全面了解潜在的分子机制对于开发针对 ER 应激反应的治疗干预措施是必要的。在这篇综述中，我们讨论了 ER 应激和 UPR 信号在代谢综合征发病机制中的作用，强调了 UPR 成分的主要功能。我们强调了使用新型小分子化学伴侣，它们被认为是 ER 应激调节剂。这些化学伴侣的初步研究很有希望，但需要进行详细研究，以确定它们在人类治疗中的疗效和不良反应。
