Atherosclerosis predisposes to myriad cardiovascular complications, including myocardial infarction and stroke. Statins have revolutionised cholesterol management but they do not work for all patients, particularly those with familial hypercholesterolaemia (FH). Genome-wide association studies have linked SNPs at orphan G protein-coupled receptor 146 (GPR146) to human atherosclerosis but how GPR146 influences serum cholesterol homeostasis was only recently described. Gpr146 deletion in mice reduces serum cholesterol and atherosclerotic plaque burden, confirming GPR146 as a potential therapeutic target for managing circulating cholesterol. Critically, this effect was independent of the low-density lipoprotein receptor. While still an orphan, the activation of GPR146 by serum suggests identification of its endogenous ligand is tantalisingly close. Herein, we discuss the evidence for GPR146 inhibition as a treatment for atherosclerosis.

动脉粥样硬化易导致无数心血管并发症，包括心肌梗塞和中风。他汀类药物已经彻底改变了胆固醇管理，但它们并不适用于所有患者，尤其是那些患有家族性高胆固醇血症 (FH) 的患者。全基因组关联研究已将孤儿 G 蛋白偶联受体 146 (GPR146) 上的 SNP 与人类动脉粥样硬化联系起来，但最近才描述了 GPR146 如何影响血清胆固醇稳态。Gpr146小鼠的缺失降低了血清胆固醇和动脉粥样硬化斑块的负担，证实了 GPR146 是控制循环胆固醇的潜在治疗靶点。至关重要的是，这种效应与低密度脂蛋白受体无关。虽然仍然是一个孤儿，但血清对 GPR146 的激活表明其内源性配体的鉴定非常接近。在这里，我们讨论了 GPR146 抑制作为动脉粥样硬化治疗的证据。