scholarly journals Programming of Fetal Insulin Resistance in Pregnancies with Maternal Obesity by ER Stress and Inflammation

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Francisco Westermeier ◽  
Pablo J. Sáez ◽  
Roberto Villalobos-Labra ◽  
Luis Sobrevia ◽  
Marcelo Farías-Jofré
Keyword(s):  
Insulin Resistance ◽  
Er Stress ◽  
Maternal Obesity ◽  
Critical Role ◽  
Cellular Processes ◽  
Unfolded Protein ◽  
Complex Interactions ◽  
Fetal Complications ◽  
Stress Dependent ◽  
Protein Response

The global epidemics of obesity during pregnancy and excessive gestational weight gain (GWG) are major public health problems worldwide. Obesity and excessive GWG are related to several maternal and fetal complications, including diabetes (pregestational and gestational diabetes) and intrauterine programming of insulin resistance (IR). Maternal obesity (MO) and neonatal IR are associated with long-term development of obesity, diabetes mellitus, and increased global cardiovascular risk in the offspring. Multiple mechanisms of insulin signaling pathway impairment have been described in obese individuals, involving complex interactions of chronically elevated inflammatory mediators, adipokines, and the critical role of the endoplasmic reticulum (ER) stress-dependent unfolded protein response (UPR). However, the underlying cellular processes linking MO and IR in the offspring have not been fully elucidated. Here, we summarize the state-of-the-art evidence supporting the possibility that adverse metabolic postnatal outcomes such as IR in the offspring of pregnancies with MO and/or excessive GWG may be related to intrauterine activation of ER stress response.

scholarly journals Endoplasmic Reticulum Stress and Lipid Metabolism: Mechanisms and Therapeutic Potential

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Sana Basseri ◽  
Richard C. Austin
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Lipid Metabolism ◽  
Er Stress ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Signal Transduction Pathway ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Stress Dependent

The endoplasmic reticulum (ER) plays a crucial role in protein folding, assembly, and secretion. Disruption of ER homeostasis may lead to accumulation of misfolded or unfolded proteins in the ER lumen, a condition referred to as ER stress. In response to ER stress, a signal transduction pathway known as the unfolded protein response (UPR) is activated. UPR activation allows the cell to cope with an increased protein-folding demand on the ER. Recent studies have shown that ER stress/UPR activation plays a critical role in lipid metabolism and homeostasis. ER-stress-dependent dysregulation of lipid metabolism may lead to dyslipidemia, insulin resistance, cardiovascular disease, type 2 diabetes, and obesity. In this paper, we examine recent findings illustrating the important role ER stress/UPR signalling pathways play in regulation of lipid metabolism, and how they may lead to dysregulation of lipid homeostasis.

scholarly journals Endoplasmic reticulum stress and the development of endothelial dysfunction

2017 ◽  
Vol 312 (3) ◽  
pp. H355-H367 ◽  
Author(s):  
M. L. Battson ◽  
D. M. Lee ◽  
C. L. Gentile
Keyword(s):  
Endoplasmic Reticulum ◽  
Endothelial Dysfunction ◽  
Er Stress ◽  
Critical Role ◽  
Unfolded Protein ◽  
Vasoactive Substances ◽  
Important Regulator ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis

The vascular endothelium plays a critical role in cardiovascular homeostasis, and thus identifying the underlying causes of endothelial dysfunction has important clinical implications. In this regard, the endoplasmic reticulum (ER) has recently emerged as an important regulator of metabolic processes. Dysfunction within the ER, broadly termed ER stress, evokes the unfolded protein response (UPR), an adaptive pathway that aims to restore ER homeostasis. Although the UPR is the first line of defense against ER stress, chronic activation of the UPR leads to cell dysfunction and death and has recently been implicated in the pathogenesis of endothelial dysfunction. Numerous risk factors for endothelial dysfunction can induce ER stress, which may in turn disrupt endothelial function via direct effects on endothelium-derived vasoactive substances or by activating other pathogenic cellular networks such as inflammation and oxidative stress. This review summarizes the available data linking ER stress to endothelial dysfunction.

scholarly journals Expression of Human Mutant Preproinsulins Induced Unfolded Protein Response, Gadd45 Expression, JAK-STAT Activation, and Growth Inhibition in Drosophila

2021 ◽  
Vol 22 (21) ◽  
pp. 12038
Author(s):  
Tatsuki Yamazoe ◽  
Yasuyuki Nakahara ◽  
Hiroka Katsube ◽  
Yoshihiro H. Inoue
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Inflammatory Responses ◽  
Expression System ◽  
Ectopic Expression ◽  
Induced Expression ◽  
Unfolded Protein ◽  
Stress Dependent ◽  
Protein Response ◽  
Mutant Polypeptides

Mutations in the insulin gene (INS) are frequently associated with human permanent neonatal diabetes mellitus. However, the mechanisms underlying the onset of this genetic disease is not sufficiently decoded. We induced expression of two types of human mutant INSs in Drosophila using its ectopic expression system and investigated the resultant responses in development. Expression of the wild-type preproinsulin in the insulin-producing cells (IPCs) throughout the larval stage led to a stimulation of the overall and wing growth. However, ectopic expression of human mutant preproinsulins, hINSC96Y and hINSLB15YB16delinsH, neither of which secreted from the β-cells, could not stimulate the Drosophila growth. Furthermore, neither of the mutant polypeptides induced caspase activation leading to apoptosis. Instead, they induced expression of several markers indicating the activation of unfolded protein response, such as ER stress-dependent Xbp1 mRNA splicing and ER chaperone induction. We newly found that the mutant polypeptides induced the expression of Growth arrest and DNA-damage-inducible 45 (Gadd45) in imaginal disc cells. ER stress induced by hINSC96Y also activated the JAK-STAT signaling, involved in inflammatory responses. Collectively, we speculate that the diabetes-like growth defects appeared as a consequence of the human mutant preproinsulin expression was involved in dysfunction of the IPCs, rather than apoptosis.

scholarly journals The Cross-Links of Endoplasmic Reticulum Stress, Autophagy, and Nurodegeneration in Parkinson’s Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Haigang Ren ◽  
Wanqing Zhai ◽  
Xiaojun Lu ◽  
Guanghui Wang
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Substantia Nigra Pars Compacta ◽  
Cellular Processes ◽  
Unfolded Protein ◽  
Cross Links ◽  
Main Component ◽  
Protein Response

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, and it is characterized by the selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc), as well as the presence of intracellular inclusions with α-synuclein as the main component in surviving DA neurons. Emerging evidence suggests that the imbalance of proteostasis is a key pathogenic factor for PD. Endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) and autophagy, two major pathways for maintaining proteostasis, play important roles in PD pathology and are considered as attractive therapeutic targets for PD treatment. However, although ER stress/UPR and autophagy appear to be independent cellular processes, they are closely related to each other. In this review, we focused on the roles and molecular cross-links between ER stress/UPR and autophagy in PD pathology. We systematically reviewed and summarized the most recent advances in regulation of ER stress/UPR and autophagy, and their cross-linking mechanisms. We also reviewed and discussed the mechanisms of the coexisting ER stress/UPR activation and dysregulated autophagy in the lesion regions of PD patients, and the underlying roles and molecular crosslinks between ER stress/UPR activation and the dysregulated autophagy in DA neurodegeneration induced by PD-associated genetic factors and PD-related neurotoxins. Finally, we indicate that the combined regulation of ER stress/UPR and autophagy would be a more effective treatment for PD rather than regulating one of these conditions alone.

scholarly journals Heat Shock Protein 90 Modulates the Unfolded Protein Response by Stabilizing IRE1α

2002 ◽  
Vol 22 (24) ◽  
pp. 8506-8513 ◽  
Author(s):  
Monica G. Marcu ◽  
Melissa Doyle ◽  
Anne Bertolotti ◽  
David Ron ◽  
Linda Hendershot ◽  
...  
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Specific Inhibitor ◽  
Transcriptional Response ◽  
Heat Shock Protein 90 ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Stress Dependent ◽  
And Function ◽  
Protein Response

ABSTRACT The molecular chaperone HSP90 regulates stability and function of multiple protein kinases. The HSP90-binding drug geldanamycin interferes with this activity and promotes proteasome-dependent degradation of most HSP90 client proteins. Geldanamycin also binds to GRP94, the HSP90 paralog located in the endoplasmic reticulum (ER). Because two of three ER stress sensors are transmembrane kinases, namely IRE1α and PERK, we investigated whether HSP90 is necessary for the stability and function of these proteins. We found that HSP90 associates with the cytoplasmic domains of both kinases. Both geldanamycin and the HSP90-specific inhibitor, 514, led to the dissociation of HSP90 from the kinases and a concomitant turnover of newly synthesized and existing pools of these proteins, demonstrating that the continued association of HSP90 with the kinases was required to maintain their stability. Further, the previously reported ability of geldanamycin to stimulate ER stress-dependent transcription apparently depends on its interaction with GRP94, not HSP90, since geldanamycin but not 514 led to up-regulation of BiP. However, this effect is eventually superseded by HSP90-dependent destabilization of unfolded protein response signaling. These data establish a role for HSP90 in the cellular transcriptional response to ER stress and demonstrate that chaperone systems on both sides of the ER membrane serve to integrate this signal transduction cascade.

scholarly journals The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 333 ◽  
Author(s):  
Alberto M. Martelli ◽  
Francesca Paganelli ◽  
Francesca Chiarini ◽  
Camilla Evangelisti ◽  
James A. McCubrey
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Critical Role ◽  
Cell Protein ◽  
Acute Leukemias ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Novel Therapeutic

The unfolded protein response (UPR) is an evolutionarily conserved adaptive response triggered by the stress of the endoplasmic reticulum (ER) due, among other causes, to altered cell protein homeostasis (proteostasis). UPR is mediated by three main sensors, protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6α (ATF6α), and inositol-requiring enzyme-1α (IRE1α). Given that proteostasis is frequently disregulated in cancer, UPR is emerging as a critical signaling network in controlling the survival, selection, and adaptation of a variety of neoplasias, including breast cancer, prostate cancer, colorectal cancer, and glioblastoma. Indeed, cancer cells can escape from the apoptotic pathways elicited by ER stress by switching UPR into a prosurvival mechanism instead of cell death. Although most of the studies on UPR focused on solid tumors, this intricate network plays a critical role in hematological malignancies, and especially in multiple myeloma (MM), where treatment with proteasome inhibitors induce the accumulation of unfolded proteins that severely perturb proteostasis, thereby leading to ER stress, and, eventually, to apoptosis. However, UPR is emerging as a key player also in acute leukemias, where recent evidence points to the likelihood that targeting UPR-driven prosurvival pathways could represent a novel therapeutic strategy. In this review, we focus on the oncogene-specific regulation of individual UPR signaling arms, and we provide an updated outline of the genetic, biochemical, and preclinical therapeutic findings that support UPR as a relevant, novel target in acute leukemias.

Endoplasmic reticulum stress signaling: the microRNA connection

2013 ◽  
Vol 304 (12) ◽  
pp. C1117-C1126 ◽  
Author(s):  
Marion Maurel ◽  
Eric Chevet
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Small Noncoding Rnas ◽  
Unfolded Protein ◽  
Transcriptional Reprogramming ◽  
Stress Sensors ◽  
Activating Transcription Factor ◽  
Stress Dependent ◽  
Protein Response ◽  
Er Homeostasis

The endoplasmic reticulum (ER)-induced unfolded protein response (ERUPR) is an adaptive mechanism that is activated upon accumulation of misfolded proteins in the ER and aims at restoring ER homeostasis. The ERUPR is transduced by three major ER-resident stress sensors, namely PKR-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6), and inositol requiring enzyme 1 (IRE1). Activation of these ER stress sensors leads to transcriptional reprogramming of the cells. Recently, microRNAs (miRNAs), small noncoding RNAs that generally repress gene expression, have emerged as key regulators of ER homeostasis and important players in ERUPR-dependent signaling. Moreover, the miRNAs biogenesis machinery appears to also be regulated upon ER stress. Herein we extensively review the relationships existing between “canonical” ERUPR signaling, control of ER homeostasis, and miRNAs. We reveal an intricate signaling network that might confer specificity and selectivity to the ERUPR in tissue- or stress-dependent fashion. We discuss these issues in the context of the physiological and pathophysiological roles of ERUPR signaling.

scholarly journals Sigma-1 Receptor Is Critical for Mitochondrial Activity and Unfolded Protein Response in Larval Zebrafish

2021 ◽  
Vol 22 (20) ◽  
pp. 11049
Author(s):  
Lucie Crouzier ◽  
Morgane Denus ◽  
Elodie M. Richard ◽  
Amarande Tavernier ◽  
Camille Diez ◽  
...  
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Transmembrane Protein ◽  
Critical Role ◽  
Mitochondrial Activity ◽  
Sigma 1 Receptor ◽  
Unfolded Protein ◽  
Sigma 1 ◽  
Protein Response ◽  
The Impact

The sigma-1 receptor (S1R) is a highly conserved transmembrane protein highly enriched in mitochondria-associated endoplasmic reticulum (ER) membranes, where it interacts with several partners involved in ER-mitochondria Ca2+ transfer, activation of the ER stress pathways, and mitochondria function. We characterized a new S1R deficient zebrafish line and analyzed the impact of S1R deficiency on visual, auditory and locomotor functions. The s1r+25/+25 mutant line showed impairments in visual and locomotor functions compared to s1rWT. The locomotion of the s1r+25/+25 larvae, at 5 days post fertilization, was increased in the light and dark phases of the visual motor response. No deficit was observed in acoustic startle response. A critical role of S1R was shown in ER stress pathways and mitochondrial activity. Using qPCR to analyze the unfolded protein response genes, we observed that loss of S1R led to decreased levels of IRE1 and PERK-related effectors and increased over-expression of most of the effectors after a tunicamycin challenge. Finally, S1R deficiency led to alterations in mitochondria bioenergetics with decreased in basal, ATP-linked and non-mitochondrial respiration and following tunicamycin challenge. In conclusion, this new zebrafish model confirmed the importance of S1R activity on ER-mitochondria communication. It will be a useful tool to further analyze the physiopathological roles of S1R.

scholarly journals The Role of Mitochondrial Dysfunction and ER Stress in TDP-43 and C9ORF72 ALS

2021 ◽  
Vol 15 ◽  
Author(s):  
Ruxandra Dafinca ◽  
Paola Barbagallo ◽  
Kevin Talbot
Keyword(s):  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Unfolded Protein Response ◽  
Nucleocytoplasmic Transport ◽  
Cellular Processes ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system with complex determinants, including genetic and non-genetic factors. Despite this heterogeneity, a key pathological signature is the mislocalization and aggregation of specific proteins in the cytoplasm, suggesting that convergent pathogenic mechanisms focusing on disturbances in proteostasis are important in ALS. In addition, many cellular processes have been identified as potentially contributing to disease initiation and progression, such as defects in axonal transport, autophagy, nucleocytoplasmic transport, ER stress, calcium metabolism, the unfolded protein response and mitochondrial function. Here we review the evidence from in vitro and in vivo models of C9ORF72 and TDP-43-related ALS supporting a central role in pathogenesis for endoplasmic reticulum stress, which activates an unfolded protein response (UPR), and mitochondrial dysfunction. Disruption in the finely tuned signaling between the ER and mitochondria through calcium ions may be a crucial trigger of mitochondrial deficits and initiate an apoptotic signaling cascade, thus acting as a point of convergence for multiple upstream disturbances of cellular homeostasis and constituting a potentially important therapeutic target.

scholarly journals Beneficial effect of ER stress preconditioning in protection against FFA-induced adipocyte inflammation via XBP1 in 3T3-L1 adipocytes

2019 ◽  
Vol 463 (1-2) ◽  
pp. 45-55
Author(s):  
Min Wang ◽  
Xi Chen ◽  
Zhenda Zheng ◽  
Shujie Yu ◽  
Bin Zhou ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Er Stress ◽  
Inflammatory Cytokine ◽  
Low Dose ◽  
Protective Effects ◽  
Unfolded Protein ◽  
Retinal Inflammation ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Adipose tissue inflammation is closely associated with the development of obesity and insulin resistance. Free fatty acids (FFAs) are a major inducer of obesity-related insulin resistance. Previously, we reported that endoplasmic reticulum (ER) stress potentially mediated retinal inflammation in diabetic retinopathy. The unfolded protein response (UPR) protects cells against damage induced by oxidative stress. X-box binding protein 1 (XBP1) plays a major role in protecting cells by modulating the UPR. However, the link between ER stress and adipocyte inflammation has been poorly investigated. In the present study, we found that pretreatment of 3T3-L1 adipocytes with a low dose of ER stress inducer tunicamycin inhibited FFA-induced upregulated expression of inflammatory cytokines. In addition, FFAs induced phosphorylation of the p65 subunit of NF-κB was largely inhibited by pretreatment with tunicamycin in 3T3-L1 adipocytes. Knockdown of XBP1 by siRNA markedly mitigated the protective effects of preconditioning against inflammation. Conversely, overexpression of XBP1 alleviated FFA-induced phosphorylation of IκB-α, IKKα/β, and NF-κB, which was accompanied by decreased inflammatory cytokine expression. Collectively, these results imply a beneficial role of ER stress preconditioning in protecting against FFA-induced 3T3-L1 adipocyte inflammation, which is likely mediated through inhibition of the IKK/NF-κB pathway via XBP1.

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