Endoplasmic Reticulum Stress and the Inflammatory Basis of Metabolic Disease

Hotamışlıgil, Gökhan S.

doi:10.1016/j.cell.2010.02.034

Cited by 2,363 publications

(2,262 citation statements)

References 152 publications

Supporting

Mentioning

2,158

Contrasting

Unclassified

Order By: Relevance

“…Currently, much of the data on the regulation of ER stress in human metabolic diseases and endothelial function have been focused on the involvement of the IRE1α and PERK branches of the UPR 35. In this study, we have demonstrated an enhanced activation of acute ER stress markers IRE1α and PERK, and a lack of differential expression in ATF6 in patients with DM when compared with controls without DM.…”

Section: Discussionmentioning

confidence: 54%

“…In the past decade, the ER has been identified as an important regulator of metabolic processes,35 and Gargalovic et al were among the first to directly link ER stress to endothelial disturbances 36. Experimental studies in cultured endothelial cells have demonstrated that chemically induced ER stress causes endothelial dysfunction and insulin resistance 37, 38.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus

Bretón‐Romero

Weisbrod

Feng

et al. 2018

JAHA

View full text Add to dashboard Cite

BackgroundPrior studies have shown that nutrient excess induces endoplasmic reticulum (ER) stress in nonvascular tissues from patients with diabetes mellitus (DM). ER stress and the subsequent unfolded protein response may be protective, but sustained activation may drive vascular injury. Whether ER stress contributes to endothelial dysfunction in patients with DM remains unknown.Methods and ResultsTo characterize vascular ER stress, we isolated endothelial cells from 42 patients with DM and 37 subjects without DM. Endothelial cells from patients with DM displayed higher levels of ER stress markers compared with controls without DM. Both the early adaptive response, evidenced by higher phosphorylated protein kinase–like ER eukaryotic initiation factor‐2a kinase and inositol‐requiring ER‐to‐nucleus signaling protein 1 (P=0.02, P=0.007, respectively), and the chronic ER stress response evidenced by higher C/EBPα‐homologous protein (P=0.02), were activated in patients with DM. Higher inositol‐requiring ER‐to‐nucleus signaling protein 1 activation was associated with lower flow–mediated dilation, consistent with endothelial dysfunction (r=0.53, P=0.02). Acute treatment with liraglutide, a glucagon‐like peptide 1 receptor agonist, reduced p‐inositol‐requiring ER‐to‐nucleus signaling protein 1 (P=0.01), and the activation of its downstream target c‐jun N‐terminal kinase (P=0.025) in endothelial cells from patients with DM. Furthermore, liraglutide restored insulin‐stimulated endothelial nitric oxide synthase activation in patients with DM (P=0.019).ConclusionsIn summary, our data suggest that ER stress contributes to vascular insulin resistance and endothelial dysfunction in patients with DM. Further, we have demonstrated that liraglutide ameliorates ER stress, decreases c‐jun N‐terminal kinase activation and restores insulin‐mediated endothelial nitric oxide synthase activation in endothelial cells from patients with DM.

show abstract

Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus

Bretón‐Romero

Weisbrod

Feng

et al. 2018

JAHA

View full text Add to dashboard Cite

show abstract

“…Abnormal glycosylation is associated with malignance, tumor progression, metastasis, and also results in UPR activation 40, 42, 43, 44. UPR is an important tightly regulated response required for cellular homeostasis, and it intersects with many other pathways that are critical for glucose metabolism, glycogen synthesis, lipid metabolism, inflammation, and metabolic disease 45. Recent studies have shown that the UPR plays a role in liver disease,46, 47 that its activation is associated with hepatic insulin resistance and fatty acid flux,48, 49 and that the UPR mediator XBP1 can up‐regulate hepatic lipogenic factor 47, 50.…”

Section: Discussionmentioning

confidence: 99%

Up‐regulation of golgi α‐mannosidase IA and down‐regulation of golgi α‐mannosidase IC activates unfolded protein response during hepatocarcinogenesis

Hsiao

Yang

et al. 2017

Hepatology Communications

View full text Add to dashboard Cite

α‐1,2 mannosidases, key enzymes in N‐glycosylation, are required for the formation of mature glycoproteins in eukaryotes. Aberrant regulation of α‐1,2 mannosidases can result in cancer, although the underlying mechanisms are unclear. Here, we report the distinct roles of α‐1,2 mannosidase subtypes (MAN1A, MAN1B, ERMAN1, MAN1C) in the formation of hepatocellular carcinoma (HCC). Clinicopathological analyses revealed that the clinical stage, tumor size, α‐fetoprotein level, and invasion status were positively correlated with the expression levels of MAN1A1, MAN1B1, and MAN1A2. In contrast, the expression of MAN1C1 was decreased as early as stage I of HCC. Survival analyses showed that high MAN1A1, MAN1A2, and MAN1B1 expression levels combined with low MAN1C1 expression levels were significantly correlated with shorter overall survival rates. Functionally, the overexpression of MAN1A1 promoted proliferation, migration, and transformation as well as in vivo migration in zebrafish. Conversely, overexpression of MAN1C1 reduced the migration ability both in vitro and in vivo, decreased the colony formation ability, and shortened the S phase of the cell cycle. Furthermore, the expression of genes involved in cell cycle/proliferation and migration was increased in MAN1A1‐overexpressing cells but decreased in MAN1C1‐overexpressing cells. MAN1A1 activated the expression of key regulators of the unfolded protein response (UPR), while treatment with endoplasmic reticulum stress inhibitors blocked the expression of MAN1A1‐activated genes. Using the MAN1A1 liver‐specific overexpression zebrafish model, we observed steatosis and inflammation at earlier stages and HCC formation at a later stage accompanied by the increased expression of the UPR modulator binding immunoglobulin protein (BiP). These data suggest that the up‐regulation of MAN1A1 activates the UPR and might initiate metastasis. Conclusion: MAN1A1 represents a novel oncogene while MAN1C1 plays a role in tumor suppression in hepatocarcinogenesis. (Hepatology Communications 2017;1:230‐247)

show abstract

“…When misfolded proteins accumulate in the cytosol or in the ER these trigger two distinct damage-responses, namely the heat shock response 52,53 and the unfolded protein response (UPR) 51,54,55 , respectively (Fig.4). The hallmarks of these proteotoxic responses are: i) broad suppression of protein synthesis and ii) transcriptional up-regulation of a subset of immediate early-responsive genes that escape translational repression, and repair protein damage and/or destroy unfolded proteins 29,51 .…”

Section: Damage-responses and Tissue Damage Controlmentioning

confidence: 99%

“…is sensed by the binding immunoglobulin protein (BiP)/78 kDa glucose-regulated protein (GRP-78) chaperone and the inositol requiring protein-1 (IRE1), two master regulators of the UPR 54,55 . Dimerization and release of GRP78, de-repress IRE1 activity 55 , which splices X-box binding protein 1 (XBP1) mRNA, promoting XBP1 translation, nuclear translocation and binding to DNA X-box elements in the promoter of effector genes regulating the UPR.…”

Section: Unfolded Protein Response (Upr) Accumulation Of Misfolded Pmentioning

confidence: 99%

Tissue damage control in disease tolerance

Soares

Gozzelino

Weis

2014

Trends in Immunology

152

162

View full text Add to dashboard Cite

The deposited article is a prost-print version.This publication hasn't any creative commons license associated.This deposit is composed by the main article, and it hasn't any supplementary materials associated.Immune-driven resistance mechanisms are the prevailing host defense strategy against infection. By contrast, disease tolerance mechanisms limit disease severity by preventing tissue damage or ameliorating tissue function without interfering with pathogen load. We propose here that tissue damage control underlies many of the protective effects of disease tolerance. We explore the mechanisms of cellular adaptation that underlie tissue damage control in response to infection as well as sterile inflammation, integrating both stress and damage responses. Finally, we discuss the potential impact of targeting these mechanisms in the treatment of disease.Fundação para a Ciência e Tecnologia grants: (PTDC/SAU-TOX/116627/2010, HMSP-ICT/0022/2010, SFRH/BPD/44256/2008); European Commission 7th Framework grant: (ERC-2011-AdG. 294709-DAMAGECONTROL); Deutsche Forschungsgemeinschaft grant: (DFG WE 4971/3-1).info:eu-repo/semantics/publishedVersio

show abstract

Endoplasmic Reticulum Stress and the Inflammatory Basis of Metabolic Disease

Cited by 2,363 publications

References 152 publications

Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus

Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus

Up‐regulation of golgi α‐mannosidase IA and down‐regulation of golgi α‐mannosidase IC activates unfolded protein response during hepatocarcinogenesis

Tissue damage control in disease tolerance

Contact Info

Product

Resources

About