GP73 is a glucogenic hormone that contributes to SARS-CoV-2-induced hyperglycemia (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces new-onset diabetes and severe metabolic complications of pre-existing diabetes. The pathogenic mechanism underlying this is incompletely understood. Here, we provided evidence linking circulating GP73 with the exaggerated gluconeogenesis triggered by SARS-CoV-2 infection. We found that SARS-CoV-2 infection or glucotoxic conditions increased GP73 production and secretion. Secreted GP73 then trafficked to the liver and kidney to stimulate gluconeogenesis through the cAMP/PKA pathway. By using global phosphoproteomics, we found a drastic remodeling of the PKA kinase hub exerted by GP73. Notably, plasma GP73 levels were elevated and positively correlated with blood glucose in patients with COVID19 and diabetes. Neutralization of circulating GP73 in serum of individuals infected with SARS-CoV-2 or with diabetes reduced excessive gluconeogenesis in cultured hepatocytes, and lowered blood glucose levels in animal models of diabetes. Ablation of GP73 from whole animals has a profound glucose-lowering effect secondary to reduced gluconeogenesis. Thus, GP73 is a key glucogenic hormone contributing to SARS-CoV-2-induced glucose abnormality.

GP73 is a glucogenic hormone regulating SARS-CoV-2-induced hyperglycemia (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces new-onset diabetes and severe metabolic complications of pre-existing diabetes. The pathogenic mechanism underlying this is incompletely understood. Here, we provided evidence linking circulating GP73 with the exaggerated gluconeogenesis triggered by SARS-CoV-2 infection. We found that SARS-CoV-2 infection or glucotoxic condition increased the cellular secretion of GP73. Secreted GP73 trafficked to the liver and kidney to stimulate gluconeogenesis through cAMP/PKA pathway. By using global phosphoproteomics, we found a drastic remodeling of PKA kinase hub exerted by GP73. Notably, COVID-19 patients showed pathologically elevated plasma GP73, and neutralization of the secreted GP73 inhibited enhanced PKA signaling and glucose production associated with SARS-CoV-2 infection. GP73 blockade also reduced gluconeogenesis and lowered hyperglycemia in type 2 (T2D) diabetic mice. Therefore, our findings provide novel insight into the roles of GP73 as a key glucogenic hormone and mechanistic clues underlying the development of SARS-CoV-induced glucose abnormalities.

SARS-CoV-2 manipulates the SR-B1-mediated HDL uptake pathway for its entry (preprint)

The recently emerged pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly, leading to a global COVID-19 pandemic. Binding of the viral spike protein (SARS-2-S) to cell surface receptor angiotensin-converting enzyme 2 (ACE2) mediates host cell infection. In the present study, we demonstrate that in addition to ACE2, the S1 subunit of SARS-2-S binds to HDL and that SARS-CoV-2 hijacks the SR-B1-mediated HDL uptake pathway to facilitate its entry. SR-B1 facilitates SARS-CoV-2 entry into permissive cells by augmenting virus attachment. MAb (monoclonal antibody)-mediated blocking of SARS-2-S-HDL binding and SR-B1 antagonists strongly inhibit HDL-enhanced SARS-CoV-2 infection. Notably, SR-B1 is co-expressed with ACE2 in human pulmonary and extrapulmonary tissues. These findings revealed a novel mechanism for SARS-CoV-2 entry and could provide a new target to treat SARS-CoV-2 infection.

Cholesterol Metabolism--Impact for SARS-CoV-2 Infection Prognosis, Entry, and Antiviral Therapies (preprint)

Abstract The recently emerged pathogenic SARS-coronavirus 2 (SARS-CoV-2) has spread rapidly, leading to a global pandemic. In this study, we show that SARS-CoV-2 infection was associated with clinically significant lower level of HDL cholesterol (HDL-C), which can be used as indicators of disease severity and poor prognosis. Importantly, we found the spike protein of SARS-CoV-2 (SARS-2-S) bound to HDL. Antagonists of HDL receptor-Scavenger receptor class B type I (SR-B1), strongly inhibited SARS-CoV-2 infection. Notably, the lipids transfer function of SR-B1 was indispensable for this inhibition, offering explanations for the reduced serum HDL level observed in COVID-19 patients. Basing on findings here, we speculate that SR-B1-mediated pulmonary HDL-vitamin E uptake could participate in mediating SARS-CoV-2 infection of lung cells, and the unique expression profile of SR-B1 may also affect SARS-CoV-2 cell and tissue tropism. These findings might help to provide further insights into viral transmission, pathological characteristics and reveal therapeutic targets.