Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS), Beijing, China.
Beijing Sungen Biomedical Technology Co. Ltd., Beijing, China.
Nat Metab. 2022 Jan;4(1):29-43. doi: 10.1038/s42255-021-00508-2. Epub 2022 Jan 6.
Severe cases of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are associated with elevated blood glucose levels and metabolic complications. However, the molecular mechanisms for how SARS-CoV-2 infection alters glycometabolic control are incompletely understood. Here, we connect the circulating protein GP73 with enhanced hepatic gluconeogenesis during SARS-CoV-2 infection. We first demonstrate that GP73 secretion is induced in multiple tissues upon fasting and that GP73 stimulates hepatic gluconeogenesis through the cAMP/PKA signaling pathway. We further show that GP73 secretion is increased in cultured cells infected with SARS-CoV-2, after overexpression of SARS-CoV-2 nucleocapsid and spike proteins and in lungs and livers of mice infected with a mouse-adapted SARS-CoV-2 strain. GP73 blockade with an antibody inhibits excessive glucogenesis stimulated by SARS-CoV-2 in vitro and lowers elevated fasting blood glucose levels in infected mice. In patients with COVID-19, plasma GP73 levels are elevated and positively correlate with blood glucose levels. Our data suggest that GP73 is a glucogenic hormone that likely contributes to SARS-CoV-2-induced abnormalities in systemic glucose metabolism.
严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）感染的严重病例与血糖水平升高和代谢并发症有关。然而，SARS-CoV-2 感染如何改变糖代谢控制的分子机制尚不完全清楚。在这里，我们将循环蛋白 GP73 与 SARS-CoV-2 感染期间增强的肝糖异生联系起来。我们首先证明，在禁食时，多种组织中 GP73 的分泌被诱导，并且 GP73 通过 cAMP/PKA 信号通路刺激肝糖异生。我们进一步表明，在感染 SARS-CoV-2 的培养细胞中、在过表达 SARS-CoV-2 核衣壳和刺突蛋白后以及在感染鼠适应的 SARS-CoV-2 株的肺和肝脏中，GP73 的分泌增加。用抗体阻断 GP73 可抑制 SARS-CoV-2 体外刺激的过度糖生成，并降低感染小鼠的空腹血糖水平升高。在 COVID-19 患者中，血浆 GP73 水平升高，并与血糖水平呈正相关。我们的数据表明，GP73 是一种生糖激素，可能导致 SARS-CoV-2 引起的全身葡萄糖代谢异常。
