Two G protein-coupled receptors bind ceramides in atherosclerosis progression: targets for a new therapeutic strategy

A recent study published by Zhang et al. 1 in Nature suggested that the endogenous ceramide receptors cysteinyl leukotriene receptor 2 (CYSLTR2) and the pyrimidinergic receptor P2Y6 (P2Y6R) are potential novel targets for the treatment of atherosclerosis and related cardiovascular conditions beyond mainstream cholesterol control strategies.This new finding paves the way for another milestone in the emerging innovative search for novel atherosclerosis therapies.Atherosclerosis is the leading cause of severe cardiovascular events such as myocardial infarction and stroke.Current drug treatment strategies focus primarily on lowering low-density lipoprotein cholesterol (LDL-C).Although statins and other lipidlowering medications reduce the risk of cardiovascular adverse events by approximately one-third, a significant number of patients still face "residual risk" and experience adverse cardiovascular events even when their lipid levels are within target ranges. 2This is particularly true for patients with chronic kidney disease (CKD), where the efficacy of cholesterol reduction in preventing cardiovascular diseases diminishes as renal function declines, nearly disappearing in patients with end-stage renal disease. 3New targets or strategies to combat atherosclerosis beyond cholesterol reduction are urgently needed.Ceramides are a class of sphingolipids formed by the linkage of sphingosine chains with fatty acid chains of varying lengths through amide bonds and signal via NOD-like receptor pyrin domain 3 (NLRP3) activation. 4A recent study via cryo-electron microscopy revealed that a Gi-coupled ceramide receptor acted through N-formyl peptide receptor 2 (FPR2) to regulate thermogenesis in adipocytes. 5Previous clinical studies have shown that long-chain ceramides in circulation, such as C16:0, C18:0, and C24:1, can predict the risk of cardiovascular events and are thus referred to as "second cholesterol."However, how long-chain ceramides in circulation exacerbate the development of atherosclerotic cardiovascular diseases and whether there are membrane receptors that mediate their pathogenic signaling have long been open questions in the scientific community.In this study, the authors identified for the first time a non-orphan endogenous membrane GPCR (G protein-coupled receptor) for circulating long-chain ceramides such as CYSLTR2 and P2RY6.Upon recognition of ceramides by these receptors, Gq protein activation is triggered, leading to activation of the NLRP3 inflammasome, which causes cleavage of caspase-1 (encoded by Casp1) and production of interleukin-1 (IL-1), both of which significantly exacerbate the