Endoplasmic reticulum stress: A master regulator of metabolic syndrome

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.