The Circulating GRP78/BiP Is a Marker of Metabolic Diseases and Atherosclerosis: Bringing Endoplasmic Reticulum Stress into the Clinical Scenario

Girona, Josefa; Rodríguez-Borjabad, Cèlia; Ibarretxe, Daiana; Vallvé, Joan-Carles; Ferré, Raimón; Heras, Mercedes; Rodríguez-Calvo, Ricardo; Guaita‐Esteruelas, Sandra; Martínez-Micaelo, Neus; Plana, Núria; Masana, Luís

doi:10.3390/jcm8111793

Cited by 44 publications

(48 citation statements)

References 33 publications

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“…Obesity and various factors associated with obesity induce ER stress [ 73 ] and consequently UPR activation. These factors, including hypoxia, reactive oxygen species, insulin resistance, nutritional imbalance and excessive fat storage [ 74 , 75 , 76 ], stimulate GRP78 expression as a mechanism of the UPR to restore normal cell functions [ 77 , 78 ]. For example, evidence from in vitro and in vivo studies shows that dyslipidemia is associated with GRP78 overexpression in adipocytes (especially in white adipose tissue) [ 79 ], pneumocytes [ 80 ], neurons of the hypothalamus [ 81 ] and hepatocytes [ 82 ].…”

Section: Underlying Mechanisms Linking Obesity To Major Complications As a Results Of Sars-cov-2 Infectionmentioning

confidence: 99%

Obesity as a Risk Factor for Severe COVID-19 and Complications: A Review

Demeulemeester¹,

Punder²,

Heijningen³

et al. 2021

Cells

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Emerging data suggest that obesity is a major risk factor for the progression of major complications such as acute respiratory distress syndrome (ARDS), cytokine storm and coagulopathy in COVID-19. Understanding the mechanisms underlying the link between obesity and disease severity as a result of SARS-CoV-2 infection is crucial for the development of new therapeutic interventions and preventive measures in this high-risk group. We propose that multiple features of obesity contribute to the prevalence of severe COVID-19 and complications. First, viral entry can be facilitated by the upregulation of viral entry receptors, like angiotensin-converting enzyme 2 (ACE2), among others. Second, obesity-induced chronic inflammation and disruptions of insulin and leptin signaling can result in impaired viral clearance and a disproportionate or hyper-inflammatory response, which together with elevated ferritin levels can be a direct cause for ARDS and cytokine storm. Third, the negative consequences of obesity on blood coagulation can contribute to the progression of thrombus formation and hemorrhage. In this review we first summarize clinical findings on the relationship between obesity and COVID-19 disease severity and then further discuss potential mechanisms that could explain the risk for major complications in patients suffering from obesity.

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Section: Underlying Mechanisms Linking Obesity To Major Complications As a Results Of Sars-cov-2 Infectionmentioning

confidence: 99%

Obesity as a Risk Factor for Severe COVID-19 and Complications: A Review

Demeulemeester¹,

Punder²,

Heijningen³

et al. 2021

Cells

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“…Several studies have shown an increase in GRP78 plasma levels in patients with chronic systemic inflammation (cancer, obesity, atherosclerosis) ( 22 – 24 ). However, in acute systemic inflammation, there is increased demand for intracellular GRP78 to resolve the ERS ( 6 , 25 ).…”

Section: Discussionmentioning

confidence: 99%

A Weak Response to Endoplasmic Reticulum Stress Is Associated With Postoperative Organ Failure in Patients Undergoing Cardiac Surgery With Cardiopulmonary Bypass

et al. 2021

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Introduction: Endoplasmic reticulum stress (ERS) is involved in inflammatory organ failure. Our objective was to describe ERS, its unfolded protein response (UPR) expression/kinetics during cardiac surgery with cardiopulmonary bypass (CPB) and its association with postoperative organ failure (OF).Methods: Prospective study conducted on patients undergoing cardiac surgery with CPB. Blood samples were taken before (Pre-CPB), 2 h (H2-CPB) and 24 h (H24-CPB) after CPB. Plasma levels of 78 kDa Glucose- Regulated Protein (GRP78, final effector of UPR) were evaluated by ELISA. The expression of genes coding for key elements of UPR (ATF6, ATF4, sXBP1, CHOP) was evaluated by quantitative PCR performed on total blood. OF was defined as invasive mechanical ventilation and/or acute kidney injury and/or hemodynamic failure requiring catecholamines.Results: We included 46 patients, GRP78 was decreased at H2-CPB [1,328 (878–1,730) ng/ml vs. 2,348 (1,655–3,730) ng/ml Pre-CPB; p < 0.001] but returned to basal levels at H24-CPB [2,068 (1,436–3,005) ng/ml]. The genes involved in UPR had increased expression at H2 and H24. GRP78 plasma levels in patients with OF at H24-CPB (n = 10) remained below Pre-CPB levels [−27.6 (−51.5; −24.2)%] compared to patients without OF (n = 36) in whom GRP78 levels returned to basal levels [0.6 (−28.1; 26.6)%; p < 0.01]. H24-CPB ATF6 and CHOP expressions were lower in patients with OF than in patients without OF [2.3 (1.3–3.1) vs. 3.0 (2.7–3.7), p < 0.05 and 1.3 (0.9–2.0) vs. 2.2 (1.7–2.9), p < 0.05, respectively].Conclusions: Low relative levels of GRP78 and weak UPR gene expression appeared associated with postoperative OF. Further studies are needed to understand ERS implication during acute organ failure in humans.

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“…Increased circulating GRP78 levels are associated with hepatocellular carcinoma and liver damage caused by cholestasis, as well as nonhepatic conditions, such as obesity, metabolic disorders, rheumatoid arthritis, and lung cancer. 23 , 24 , 25 , 26 , 27 , 28 , 29 Under normal conditions, GRP78 is associated with IRE1 and protein kinase RNA-like ER kinase (PERK). 30 , 31 However, GRP78 dissociates from IRE1α and PERK, resulting in the activation of IRE1α and PERK that lead to proapoptotic pathways/mechanisms in conditions of prolonged and unresolved ER stress.…”

Section: Discussionmentioning

confidence: 99%

Induction of ER Stress by an AAV5 BDD FVIII Construct Is Dependent on the Strength of the Hepatic-Specific Promoter

Fong

Handyside

Sihn

et al. 2020

Molecular Therapy - Methods & Clinical Development

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Adeno-associated virus 5 (AAV5)-human factor VIII-SQ (hFVIII-SQ; valoctocogene roxaparvovec) is an AAV-mediated product under evaluation for treatment of severe hemophilia A, which contains a B-domain-deleted hFVIII (hFVIII-SQ) transgene and a hybrid liver-specific promotor (HLP). To increase FVIII-SQ expression and reduce the vector dose required, a stronger promoter may be considered. However, because FVIII-SQ is a protein known to be difficult to fold and secrete, this could potentially induce endoplasmic reticulum (ER) stress. We evaluated the effect of two AAV5-hFVIII-SQ vectors with different liver-specific promoter strength (HLP << 100ATGB) on hepatic ER stress in mice. Five weeks after receiving vehicle or vector, the percentage of transduced hepatocytes and levels of liver hFVIII-SQ DNA and RNA increased dose dependently for both vectors. At lower doses, plasma hFVIII-SQ protein levels were higher for 100ATGB. This difference was attenuated at the highest dose. For 100ATGB, liver hFVIII-SQ protein accumulated dose dependently, with increased expression of ER stress markers at the highest dose, suggesting hepatocytes reached or exceeded their capacity to fold/secrete hFVIII-SQ. These data suggest that weaker promoters may require relatively higher doses to distribute expression load across a greater number of hepatocytes, whereas relatively stronger promoters may produce comparable levels of FVIII in fewer hepatocytes, with potential for ER stress.

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The Circulating GRP78/BiP Is a Marker of Metabolic Diseases and Atherosclerosis: Bringing Endoplasmic Reticulum Stress into the Clinical Scenario

Cited by 44 publications

References 33 publications

Obesity as a Risk Factor for Severe COVID-19 and Complications: A Review

Obesity as a Risk Factor for Severe COVID-19 and Complications: A Review

A Weak Response to Endoplasmic Reticulum Stress Is Associated With Postoperative Organ Failure in Patients Undergoing Cardiac Surgery With Cardiopulmonary Bypass

Induction of ER Stress by an AAV5 BDD FVIII Construct Is Dependent on the Strength of the Hepatic-Specific Promoter

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