Lipin-1 restrains lipid synthesis to promote proresolving macrophage function and disease resolution

Abstract

Macrophages are critical to maintaining and restoring tissue homeostasis during inflammation. Unresolved inflammation contributes to the pathophysiology of cardiometabolic diseases. The lipid metabolic state of macrophages influences their function. Lipid synthesis contributes to proinflammatory responses, while beta-oxidation is required for pro-resolving macrophage function. However, how lipid metabolism is regulated during macrophage activation is not well understood. Lipin-1 is a phosphatidic acid phosphatase with a transcriptional coregulatory activity that is proposed to act as a regulator of lipid metabolism. We have previously demonstrated that lipin-1 is atheroprotective and promotes wound healing. Within macrophages, lipin-1 is required for beta-oxidation and apoptotic cell engulfment, both key activities of pro-resolving macrophages. We investigated the contribution of lipin-1 in regulating lipid metabolism during pro-resolving macrophage responses using metabolomics, lipidomics, and Western blot analysis. IL-4 stimulation of macrophage promotes lipid catabolism; however, in lipin-1 KO bone marrow-derived macrophages, we observed the production of metabolites that contribute to lipid synthesis, decrease phosphorylation of ACC (a marker of lipid synthesis) and a build-up of free fatty acids. We also observed increased ceramides in lipin-1 KO macrophages and a decrease in pras40 phosphorylation, which is consistent with increased ceramide synthesis. These results suggest that lipin-1 restrains de novo lipid synthesis and ceramide production to promote beta-oxidation for optimal pro-resolving macrophage function. Supported by1-R01HL131844-04 grant from NHLBI/NIH