Life science
Medical & healthcare, Drug development

Adipose GRP78, a significant host factor for COVID-19 and the association
with older age, obesity, and diabetes
Department of Diabetes Care Medicine, Graduate School of Medicine
Assistant Professor Jihoon Shin

https://researchmap.jp/shinjihoon0209

Department of Metabolic Medicine, Graduate School of Medicine
Professor Iichiro Shimomura

https://researchmap.jp/shimomura_i

Life science

Abstract
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 (coronavirus disease 2019
[COVID-19]), but the underlying mechanism has not been fully understood. In this study, we found that the SARS-CoV-2 spike protein
physically interacts with cell surface GRP78, which promotes thebinding to and accumulation in ACE2-expressing cells. GRP78 washighly expressed in adipose tissue and its expression increasedin humans and mice with older age, obesity, and diabetes. The
overexpression of GRP78 was attributed to hyperinsulinemia inadipocytes. Management of hyperinsulinemia by pharmacologicalapproaches, including metformin, sodium–glucose cotransporter2 inhibitor, or β3-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 tissue.

▍ Background & Results

Fig. 1. GRP78 as a host factor for COVID-19

Subjects with older age, obesity, and diabetes are vulnerable to
COVID-19, but the molecular basis has yet been elucidated. ACE2
is known as a major viral receptor for SARS-CoV-2. This study provides scientific evidence for the role of GRP78 as a binding partnerof the SARS-CoV-2 spike protein and ACE2, which promotes thecellular binding and accumulation. Cell surface and soluble formsof GRP78 significantly promotes the binding and accumulation ofSARS-CoV-2 spike protein to ACE2-expressing cells. The expression of GRP78 is enriched in adipose tissues and increased byconditions of older age, obesity, and diabetes, which is attributed
to the hyperinsulinemia-linked XBP-1 activity. Pharmacological or
lifestyle interventions, such as anti-diabetic drugs, exercise, andcalorie restriction, could reduce the expression of GRP78 in adipose tissues.

▍Significance of the research and Future perspective

Fig. 2. GRP78 overexpression enhances spike protein binding to ACE2.

This study would be helpful to understand the severe progression and outcome of COVID-19 in subjects with older age, obesity, and diabetes. The management of hyperinsulinemia and therelated GRP78 expression could be a therapeutic or preventative
target.

Fig. 3. Soluble GRP78 enhances spike protein binding to ACE2.

P a t e n t
Shin, Jihoon; Shimomura, Iichiro et al. Possible Involvement of Adipose Tissue in Patients With Older Age, Obesity, and Diabetes With SARS-CoV-2
T r e a t i s e Infection (COVID-19) via GRP78 (BIP/HSPA5): Significance of Hyperinsulinemia Management in COVID-19. Diabetes 2021, 70(12): 2745–2755,
doi: 10.2337/db20-1094
URL https://doi.org/10.2337/db20-1094
K e y w o r d SARS-CoV-2, COVID-19, GRP78, older age, obesity