Potential Roles of Endoplasmic Reticulum Stress and Cellular Proteins Implicated in Diabesity

Abstract

The role of the endoplasmic reticulum (ER) has evolved from protein synthesis, processing, and other secretory pathways to forming a foundation for lipid biosynthesis and other metabolic functions. Maintaining ER homeostasis is essential for normal cellular function and survival. An imbalance in the ER implied stressful conditions such as metabolic distress, which activates a protective process called unfolded protein response (UPR). This response is activated through some canonical branches of ER stress, i.e., the protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6). Therefore, chronic hyperglycemia, hyperinsulinemia, increased proinflammatory cytokines, and free fatty acids (FFAs) found in diabesity (a pathophysiological link between obesity and diabetes) could lead to ER stress. However, limited data exist regarding ER stress and its association with diabesity, particularly the implicated proteins and molecular mechanisms. Thus, this review highlights the role of ER stress in relation to some proteins involved in diabesity pathogenesis and provides insight into possible pathways that could serve as novel targets for therapeutic intervention.

Salicin modifies osteoarthritis progression by binding on IRE1α and inhibiting IRE1α mediated endoplasmic reticulum stress

“…In current study, we obtained similar results by detecting cartilage matrix degeneration and inflammatory markers. The ER is a multifunctional organelle, where protein folding occurs prior to transport to extracellular surface or to different intracellular sites [27][28][29][30] . Three ER transmembrane proteins mediated UPR, including IRE1, pancreatic endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) 28,29 .…”

“…The ER is a multifunctional organelle, where protein folding occurs prior to transport to extracellular surface or to different intracellular sites [27][28][29][30] . Three ER transmembrane proteins mediated UPR, including IRE1, pancreatic endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) 28,29 . Among them, IRE1 is the most conserved gene from yeast to human, and it has two subtypes: IRE1α and IRE1β.…”

Current Status of Endoplasmic Reticulum Stress in Type II Diabetes

“…Obesity-induced endothelial dysfunction, which is closely linked with insulin dysfunction, is attributed to ER stress [ 66 ]. The ER plays a vital role in normal insulin functioning; however, ER stress modifies insulin sensitivity negatively, which causes insulin dysfunction [ 67 , 73 ]. Thus, a detailed understanding of ER stress and insulin dysfunction’s etiology can help find a novel treatment for type II diabetes.…”

Apoptosis in Type 2 Diabetes: Can It Be Prevented? Hippo Pathway Prospects

“…Induced ER stress is manifested by an imbalance between the ability to fold proteins in relation to the needs of the cell, leading to disturbances in homeostasis [ 32 ]. Functional disproportion causes the deposition of unfolded or misfolded proteins in the lumen of the ER [ 33 ]. Unfolded protein response (UPR) is an adaptive mechanism to restore homesotase [ 31 ].…”

“…One of them is involved in the recognition of unfolded proteins. The second cytoplasmic domain sends signals to the cytosol and nucleus if the stabilization measures taken are ineffective [ 34 ]; the same communication system is used to initiate the apoptotic pathway [ 33 ]. The apoptotic pathway involves two protein families, including the Bcl-2 protein family (an acronym for B-cell lymphoma 2 gene) and caspases [ 35 ] which is the basis for distinguishing two pathways of apoptosis [ 36 ].…”