Involvement of Adipose Tissue With Coronavirus SARS-CoV-2 Infection via GRP78

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A new study by Japanese researchers from Osaka University shows that that older, obese patients with diabetes are more susceptible to severe COVID-19 infection because the SARS CoV-2 spike protein also binds to GRP78, which is highly expressed in fat tissue.

The researchers provided scientific evidence for the role of GRP78 as a binding partner of the SARS-CoV-2 spike protein and ACE2, which might be related to the severe progression and outcome of COVID-19 in older and obese patients with diabetes.

The management of hyperinsulinemia and the related GRP78 expression could be a therapeutic or preventative target.
 
The study findings were published in the peer reviewed journal: diabetes (A journal of the American Diabetes Association) https://diabetes.diabetesjournals.org/content/early/2021/10/21/db20-1094

Aging, obesity, and diabetes are major risk factors for the severe progression and outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (coro- navirus disease 2019 [COVID-19]), but the underlying mechanism is not yet fully understood.

In this study, we found that the SARS-CoV-2 spike protein physically interacts with cell surface GRP78, which promotes the binding to and accumulation in ACE2-expressing cells. GRP78 was highly expressed in adipose tissue and increased in humans and mice that were older, obese, and had diabetes.

The overexpression of GRP78 was attributed to hyperinsulinemia in adipocytes, which was in part mediated by the stress- responsive transcription factor XBP-1s. Management of hyperinsulinemia by pharmacological approaches, including
metformin, sodium–glucose cotransporter 2 inhibitor, or b3-adrenergic receptor agonist, decreased GRP78 gene expression in adipose tissue.

Environmental interventions, including exercise, calorie restriction, fasting, or cold exposure, reduced the gene expression of GRP78 in adipose tis- sue. This study provides scientific evidence for the role of GRP78 as a binding partner of the SARS-CoV-2 spike protein and ACE2, which might be related to the severe progression and outcome of COVID-19 in older and obese patients with diabetes. The management of hyperinsulinemia and the related GRP78 expression could be a therapeutic or preven- tative target.

The outbreak of the novel b-coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infec- tion, coronavirus disease 2019 (COVID-19), has rapidly spread worldwide and, to date, has resulted in over 169,000,000 human infections and more than 3,500,000 deaths. The development of SARS is the major factor for serious progression and mortality in COVID-19 patients (1).

Emerging studies have shown that there is an increased risk of poor outcomes with increasing age, obesity, visceral adiposity, and diabetes (2–4), but the linked molecular mechanisms have not yet been explained. In this severe pandemic, further scientific information and therapeutic targets are required.

While adipose tissue plays an important role in the reg- ulation of energy homeostasis, its abnormalities have harmful effects on systemic healthy states.

The aging- or obesity-associated pathological expansion of adipose tis- sue, especially in the visceral region, contributes to the development of various metabolic diseases and their com- plications (5–8).

Hyperinsulinemia, a chronic state of high insulin levels, is commonly found in older or obese patients (9,10) and causes detrimental cellular stress in adipose tissue, such as reactive oxygen species, endoplasmic reticulum (ER) stress, hypoxia, and inflammation (11–14).

Recently, adipose tissue has been taken into account as a major reservoir for viral shedding/spread, immune activation, and cytokine amplification in SARS- CoV-2 infection (COVID-19) (15–17). However, little is known about the molecular mechanisms.

SARS-CoV-2, like a previous SARS-related coronavirus (SARS-CoV), has been known to utilize angiotensin-converting enzyme 2 (ACE2) as a major host binding receptor (18). Recent studies have suggested the involvement of other binding molecules in COVID-19, such as glucose- regulated protein 78 (GRP78) (19–22).

GRP78, also known as BIP/HSPA5, is well known as a molecular chaperone localized in the ER, where it plays important roles in protein folding and assembly. Under stressed condi- tions, GRP78 is overexpressed and translocated to the cell surface and acts as a receptor for various endogenous and exogenous ligands (23,24).

GRP78 can bind many viruses and affect multiple stages of the viral life cycle, including entry, replication, egress, and subsequent spread. This property is applicable not only to Middle East respiratory syndrome coronavirus and bat coronavirus HKU9 coronaviruses but also potentially to SARS-CoV-2 (19,21,22,25).

However, scientific evidence linking GRP78 and COVID-19 and the expression profiles and possible roles of GRP78 in COVID-19 have not been fully explored.

In this study, based on the experimental results of pro- tein interactions and transcriptome analyses, we offer a perspective on the possible involvement of adipose tissue in the SARS-CoV-2 infection (COVID-19) of older and obese patients with diabetes by GRP78 and provide potential therapeutic and preventative approaches by managing hyperinsulinemia and the related GRP78 expression in adipose tissue.

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