Exploiting oxidized lipids and the lipid-binding GPCRs against CMD.

Lipids govern several vital cellular processes, in addition to drive profound physiological changes in response to different pathological or environmental cues. Lipid species can be roughly divided into structural and signalling lipids. The former is essential for membrane composition, while the latter are usually oxidized lipid species. These lipids provide beneficial effects against cardiometabolic diseases (CMD), including fatty liver diseases, atherosclerosis, thrombosis, obesity, insulin resistance and type 2 diabetes. Mono- and di-hydroxy, called oxylipins, were recently found to improve glucose homeostasis, increase insulin secretion, confer cardioprotection, and inhibit platelet aggregation. Owing to their pro-resolution capacity, specialized pro-resolving lipid mediators (SPMs) are also able to ameliorate CMD by shaping immune system. These lipid species act mainly by triggering signalling pathways through binding to G-protein coupled receptors (GPCRs). A number of GPCRs remain unknown and more than a hundred are still orphans, constituting an enormous avenue for therapeutic exploitation. Given the diversity of lipids that remain uncharacterized and the wide network of druggable signalling pathways they can trigger, the deorphanization of lipid species and a better understanding of their downstream targets are key strategies for the development of novel therapeutic approaches to combat CMD. In this review article, we provide an updated and comprehensive overview of the current state of the literature on the signalling lipids in the context of CMD. The complex network encompassing the lipid-modifying enzymes and their lipid-binding GPCRs, as well as their interactions in health and disease will be highlighted in this review.