Circulating TRB3 and GRP78 levels in type 2 diabetes patients: crosstalk between glucose homeostasis and endoplasmic reticulum stress

GRP78, a Novel Host Factor for SARS-CoV-2: The Emerging Roles in COVID-19 Related to Metabolic Risk Factors

“…GRP78 is found not only in cellular regions—the ER compartment and cell surface—but also in circulation as a soluble form of GRP78 [ 21 , 22 , 61 , 62 ]. The soluble GRP78 level increases with SARS-CoV-2 infection, which is more evident in patients with pneumonia [ 62 ].…”

“…ATF6 activation is also associated with the elevated expression of Grp78 [ 89 , 90 ]. The circulating level of GRP78 is also significantly correlated with obesity, diabetes, and other metabolic syndromes [ 22 , 61 ]. GRP78 is also well known for its high expression in many types of cancers, especially in lung cancers; the circulating levels markedly increase in association with the progression and severity [ 21 , 23 ].…”

“…SARS-CoV-2 infection is associated with the elevated expression of GRP78 in the lung and circulation [ 62 , 74 ], and presumably other infected organs and cells such as liver, adipose tissue and immune cells might exhibit similar overexpression of GRP78 through the virus-induced ER stress and unfolded protein response. The pathological implication of GRP78 overexpression in metabolic diseases has been well established in many previous studies; the expression of GRP78 is significantly increased in the adipose tissue of patients with obesity and diabetes [ 12 ]; the circulating level of GRP78 is a molecular marker of several metabolic diseases, including obesity, diabetes, and atherosclerosis [ 22 , 61 ]; the heterozygosity of the Grp78 gene increases energy expenditure and is protective against high-fat diet (HFD)-induced hyperinsulinemia, hyperglycemia, liver steatosis, and adipose inflammation with adaptive UPR [ 89 ]. Macrophage-selective ablation of the Grp78 gene improves insulin sensitivity and glucose metabolism in muscle and reduces inflammation in adipose tissue [ 91 ]; covalent inhibition of GRP78 by celastrol inhibits lipid accumulation in liver and adipose tissue with reduced ER stress and inflammation [ 92 ].…”

“…Given the physiological and pathological functions of GRP78 in the regulation of biological processes, such as protein homeostasis, cellular signaling, and transcription activity [ 13 , 14 , 17 , 18 , 19 , 20 ], it could possibly contribute to several stages of the viral life cycle and pathology of SARS-CoV-2. Furthermore, the expression of GRP78 is significantly associated with the risk factors for severe COVID-19 symptoms, such as older age, obesity, diabetes, and lung cancer [ 12 , 21 , 22 , 23 ]. Therefore, the understanding of GRP78 roles from diverse perspectives will provide a better comprehension of COVID-19 pathology and offer a novel viewpoint for the future therapeutic target.…”

AGEs-Induced and Endoplasmic Reticulum Stress/Inflammation-Mediated Regulation of GLUT4 Expression and Atherogenesis in Diabetes Mellitus

“…Apart from the proteins directly involved in glycolysis and gluconeogenesis, the heat shock proteins related to UPR and protein refolding, the ubiquitin E2 ligases involved in protein degradation by the proteasomal and lysosomal system increased upon toxic glycoxidative stress mediated by MGO generation [ 93 ]. Recently, the plasma concentration of the tribbles homolog 3 protein (TRB3) (which is enhanced by hyperglycemia and ER stress) was found increased in subjects with T2D together with AGEs, BIP and TNF; moreover, it is positively correlated with fasting plasma glucose and AGEs [ 94 ].…”