Approximately 1 in 4 people worldwide have non-alcoholic fatty liver disease (NAFLD); however, there are currently no medications to treat this condition. This study investigated the role of adiposity-associated orphan G protein-coupled receptor 75 (GPR75) in liver lipid accumulation. We profiled Gpr75 expression and report that it is most abundant in the brain. Next, we generated the first single-cell-level analysis of Gpr75 and identified a subpopulation co-expressed with key appetite-regulating hypothalamic neurons. CRISPR-Cas9-deleted Gpr75 mice fed a palatable western diet high in fat adjusted caloric intake to remain in energy balance, thereby preventing NAFLD. Consistent with mouse results, analysis of whole-exome sequencing data from 428,719 individuals (UK Biobank) revealed that variants in GPR75 are associated with a reduced likelihood of hepatic steatosis. Here, we provide a significant advance in understanding of the expression and function of GPR75, demonstrating that it is a promising pharmaceutical target for NAFLD treatment.

全球大约四分之一的人患有非酒精性脂肪肝（NAFLD）；然而，目前没有药物可以治疗这种情况。本研究调查了肥胖相关孤儿 G 蛋白偶联受体 75 (GPR75) 在肝脏脂质积累中的作用。我们分析了Gpr75 的表达，并报告它在大脑中含量最多。接下来，我们对Gpr75进行了首次单细胞水平分析，并鉴定了与关键的食欲调节下丘脑神经元共表达的亚群。 CRISPR-Cas9 缺失的Gpr75小鼠喂食可口的高脂肪西方饮食，调整热量摄入以保持能量平衡，从而预防 NAFLD。与小鼠结果一致，对 428,719 名个体的全外显子组测序数据（英国生物银行）的分析表明，GPR75的变异与肝脂肪变性可能性降低有关。在这里，我们在理解 GPR75 的表达和功能方面取得了重大进展，证明它是 NAFLD 治疗的一个有前途的药物靶点。