Activation of GPR3-β-arrestin2-PKM2 pathway in Kupffer cells stimulates glycolysis and inhibits obesity and liver pathogenesis

Ting Dong, Guangan Hu (), Zhongqi Fan, Huirui Wang, Yinghui Gao, Sisi Wang, Hao Xu, Michael B. Yaffe, Matthew G. Vander Heiden, Guoyue Lv () and Jianzhu Chen ()
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Ting Dong: Massachusetts Institute of Technology
Guangan Hu: Massachusetts Institute of Technology
Zhongqi Fan: Massachusetts Institute of Technology
Huirui Wang: School of Pharmaceutical Sciences, Shandong University
Yinghui Gao: School of Pharmaceutical Sciences, Shandong University
Sisi Wang: The First Hospital of Jilin University
Hao Xu: The First Hospital of Jilin University
Michael B. Yaffe: Massachusetts Institute of Technology
Matthew G. Vander Heiden: Massachusetts Institute of Technology
Guoyue Lv: The First Hospital of Jilin University
Jianzhu Chen: Massachusetts Institute of Technology

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Kupffer cells are liver resident macrophages and play critical role in fatty liver disease, yet the underlying mechanisms remain unclear. Here, we show that activation of G-protein coupled receptor 3 (GPR3) in Kupffer cells stimulates glycolysis and protects mice from obesity and fatty liver disease. GPR3 activation induces a rapid increase in glycolysis via formation of complexes between β-arrestin2 and key glycolytic enzymes as well as sustained increase in glycolysis through transcription of glycolytic genes. In mice, GPR3 activation in Kupffer cells results in enhanced glycolysis, reduced inflammation and inhibition of high-fat diet induced obesity and liver pathogenesis. In human fatty liver biopsies, GPR3 activation increases expression of glycolytic genes and reduces expression of inflammatory genes in a population of disease-associated macrophages. These findings identify GPR3 activation as a pivotal mechanism for metabolic reprogramming of Kupffer cells and as a potential approach for treating fatty liver disease.

Date: 2024
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DOI: 10.1038/s41467-024-45167-5

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