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. 2019 Oct 26;8(11):1793.
doi: 10.3390/jcm8111793.

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

Josefa Girona  1   2 , Cèlia Rodríguez-Borjabad  1   2 , Daiana Ibarretxe  1   2 , Joan-Carles Vallvé  1   2 , Raimon Ferré  1   2 , Mercedes Heras  1   2 , Ricardo Rodríguez-Calvo  1   2 , Sandra Guaita-Esteruelas  1 , Neus Martínez-Micaelo  1   2 , Núria Plana  1   2 , Lluís Masana  1   2
Affiliations

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

Josefa Girona et al. J Clin Med. .

Abstract

Background: Glucose-regulated protein 78/Binding immunoglobulin protein (GRP78/BiP) is a protein associated with endoplasmic reticulum stress and is upregulated by metabolic alterations at the tissue-level, such as hypoxia or glucose deprivation, and it is hyper-expressed in fat tissue of obese individuals.

Objective: To investigate the role of the GRP78/BiP level as a metabolic and vascular disease biomarker in patients with type 2 diabetes (DM), obesity and metabolic syndrome (MS).

Methods: Four hundred and five patients were recruited, of whom 52.5% were obese, 72.8% had DM, and 78.6% had MS. The intimae media thickness (cIMT) was assessed by ultrasonography. The plasma GRP78/BiP concentration was determined, and its association with metabolic and vascular parameters was assessed. Circulating GRP78/BiP was also prospectively measured in 30 DM patients before and after fenofibrate/niacin treatment and 30 healthy controls.

Results: In the cross-sectional study, the GRP78/BiP level was significantly higher in the patients with obesity, DM, and MS. Age-, gender- and BMI-adjusted GRP78/BiP was directly associated with LDL-cholesterol, non-HDL-cholesterol, triglycerides, apoB, and cIMT. GRP78/BiP was positively associated to carotid plaque presence in the adjusted model, irrespective of obesity, DM and MS. In the prospective study, nicotinic acid treatment produced a significant reduction in the GRP78/BiP levels that was not observed with fenofibrate.

Conclusions: GRP78/BiP plasma concentrations are increased in patients with both metabolic derangements and subclinical atherosclerosis. GRP78/BiP could be a useful marker of metabolic and cardiovascular risk.

Keywords: GRP78/BiP; atherosclerosis; cardiovascular risk; carotid intima–media thickness; endoplasmic reticulum stress; fenofibrate/niacin treatment; metabolic syndrome; obesity; type 2 diabetes.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Circulating 78 kDa glucose-regulated protein/binding immunoglobulin protein (GRP78/BiP) levels according to obesity (A), type 2 diabetes (B), metabolic syndrome (C) and metabolic syndrome components (D). The results are expressed as the mean ± SEM. p values for group comparisons are reported for the age- and gender-adjusted ANCOVA test.
Figure 2
Figure 2
Circulating 78 kDa glucose-regulated protein/binding immunoglobulin protein (GRP78/BiP) levels according to the presence of atherosclerotic plaques. The results are expressed as the mean ± SEM. p values for group comparison are reported for the age- and gender-adjusted ANCOVA test.
Figure 3
Figure 3
Circulating 78 kDa glucose-regulated protein/binding immunoglobulin protein (GRP78/BiP) in the control group and the type 2 diabetes patients before and after fenofibrate and nicotinic treatment in a validation cohort. The results are expressed as the mean ± SEM. p values for the group comparisons are reported for the age- and gender-adjusted ANCOVA test or paired Wilcoxon test.
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