No abstract

Phospholipases are a family of lipid-altering enzymes that can either reduce or increase bioactive lipid levels. Bioactive lipids elicit signaling responses, activate transcription factors, promote G-coupled-protein activity, and modulate membrane fluidity, which mediates cellular function. Phospholipases and the bioactive lipids they produce are important regulators of immune cell activity, dictating both pro-inflammatory and pro-resolving activity. During atherosclerosis, pro-inflammatory and pro-resolving activities govern atherosclerosis progression and regression, respectively. This review will look at the interface of phospholipase activity, immune cell function, and atherosclerosis.

Free fatty acid accumulation in macrophages alters cellular metabolism, leading to failed inflammation resolution that contributes to cardiometabolic pathologies such as atherosclerotic cardiovascular disease. Free fatty acids are either broken down by β-oxidation, stored in glycerolipids, or incorporated into sphingolipids (e.g., ceramides). Ceramide synthesis inhibits several pro-resolving macrophage functions, such as β-oxidation and efferocytosis, needed for inflammation resolution. The regulatory signals that control free fatty acid incorporation into lipids (e.g., lipid channeling) for proper macrophage function are not well understood. Lipin-1 is a phosphatidic acid phosphatase with an independent transcriptional coregulatory activity that controls cellular lipid homeostasis. Using genetically engineered mice and bone marrow-derived macrophages, we investigated the contribution of lipin-1 on macrophage pro-resolving functions. Mice lacking myeloid-specific lipin-1 had defects in the clearance of apoptotic cells in a zymosan model of inflammation resolution, and these mice had increased atherosclerotic plaques and necrotic cores in a model of atherosclerosis and a delay excisional wound closure. Bone marrow-derived macrophages lacking lipin-1 showed a striking pattern of dysregulated lipid metabolism in which il-4 stimulation promoted ceramide synthesis over β-oxidation. Additionally, lipin-1 deficient macrophages had reduced phagocytosis of apoptotic cells. Our work provides evidence that lipin-1 promotes β-oxidation while inhibiting ceramide synthesis during free fatty acid accumulation in macrophages to allow for responses that promote inflammation resolution. Supported by grants from NIH (1 R01HL131844-04) and NIH (1P20GM134974-01A1)

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

Phospholipases are a family of lipid altering enzymes that can either reduce or increase bioactive lipid levels. Bioactive lipids elicit signaling responses, activate transcription factors, promote g-coupled protein activity, and modulate membrane fluidity that mediate cellular function. Phospholipases and the bioactive lipids they produce are important regulators on immune cell activity, dictating both pro-inflammatory and pro-resolving activity. During atherosclerosis, pro-inflammatory and pro-resolving activities govern atherosclerosis progression and regression respectively. This review will look at the interface of phospholipase activity, immune cell function, and atherosclerosis.