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.

Kupffer 细胞是肝脏驻留巨噬细胞，在脂肪肝疾病中起关键作用，但其潜在机制尚不清楚。在这里，我们表明 Kupffer 细胞中 G 蛋白偶联受体 3 （GPR3） 的激活会刺激糖酵解并保护小鼠免受肥胖和脂肪肝疾病的影响。GPR3 激活通过在 β-arrestin2 和关键糖酵解酶之间形成复合物诱导糖酵解的快速增加，以及通过糖酵解基因的转录诱导糖酵解的持续增加。在小鼠中，Kupffer 细胞中的 GPR3 激活导致糖酵解增强，减少炎症并抑制高脂肪饮食诱导的肥胖和肝脏发病机制。在人脂肪肝活检中，GPR3 激活增加了糖酵解基因的表达，并降低了疾病相关巨噬细胞群中炎症基因的表达。这些发现确定 GPR3 激活是 Kupffer 细胞代谢重编程的关键机制，也是治疗脂肪肝疾病的潜在方法。