GP73 is a glucogenic hormone contributing to SARS-CoV-2-induced hyperglycemia.

Abstract

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.

• Authors: Luming Wan, Qi Gao, Yongqiang Deng, Yuehua Ke, Enhao Ma, Huan Yang, Haotian Lin, Huilong Li, Yilong Yang, Jing Gong, Jingfei Li, Yixin Xu, Jing Liu, Jianmin Li, Jialong Liu, Xuemiao Zhang, Linfei Huang, Jiangyue Feng, Yanhong Zhang, Hanqing Huang, Huapeng Wang, Changjun Wang, Qi Chen, Xingyao Huang, Qing Ye, Dongyu Li, Qiulin Yan, Muyi Liu, Meng Wei, Yunhai Mo, Dongrui Li, Ke Tang, Changqing Lin, Fei Zheng, Lei Xu, Gong Cheng, Peihui Wang, Xiaopan Yang, Feixang Wu, Zhiwei Sun, Chengfeng Qin, Congwen Wei, Hui Zhong
• Journal: Nature metabolism (Nat Metab) Vol. 4 Issue 1 Pg. 29-43 (01 2022) ISSN: 2522-5812 [Electronic] Germany
• PMID: 34992299 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• Biomarkers
• GOLM1 protein, human
• Membrane Proteins
• Cyclic AMP-Dependent Protein Kinases
• Glucose

Topics

• Animals
• Biomarkers
• COVID-19 (complications, virology)
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Diet, High-Fat
• Disease Models, Animal
• Fasting
• Gene Expression
• Gluconeogenesis (drug effects, genetics)
• Glucose (metabolism)
• Host-Pathogen Interactions
• Humans
• Hyperglycemia (blood, etiology, metabolism)
• Liver (metabolism, pathology)
• Membrane Proteins (antagonists & inhibitors, blood, genetics, metabolism)
• Mice
• Mice, Knockout
• Organ Specificity (genetics)
• SARS-CoV-2