Lipin-1 transcriptional coregulatory activity promotes macrophage pro-resolving response

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Despite medical advances, atherosclerotic cardiovascular disease (ACVD) is a leading cause of death. ACVD is caused by chronic inflammatory due to both excessive inflammation and failed inflammation resolution. Unlike inhibition of inflammation that reduces ACVD but increases fatal infections, restoration of inflammation resolution may reduce ACVD without increased fatal infections. Macrophages resolve inflammation by secreting anti-in- flammatory mediators and phagocytosing dead cells in a process termed efferocytosis. Efferocytosis increases intracellular free fatty acids (FA) that must be processed either through β-oxidation, incorporation in glycerolipids or ceramides. The movement of FA into these different pathways is called lipid channeling. Increased β-oxidation is associated with macrophage resolution and is considered atheroprotective, while ceramide metabolism pro- motes inflammation and is considered atherogenic. However, there are several critical questions: 1) Is one path- way more critical to inflammation resolution than the other, 2) does the alteration of one lipid pathway alter the other, 3) how lipid channeling is regulated during resolution and plaque regression. Lipin-1 is a phosphatidic acid phosphatase with transcriptional coregulatory activity. My laboratory showed that macrophage-associated lipin- 1 is needed for inflammation resolution and atherosclerotic regression and likely does this through regulation of FA metabolism, independent of its enzymatic activity. Our central hypothesis is that lipin-1 is a dominant lipid channeling regulator in macrophages, promoting inflammation resolution and atherosclerosis regression by en- hancing β-oxidation and repressing ceramide synthesis. We will test our central hypothesis and accomplish the objective of this application by pursuing three specific aims. Aim 1 will explore the hypothesis that lipin-1 regu- lates the activity of metabolic transcription factors to fine-tune FA metabolic pathways to align with macrophage resolution activity. Aim 2 will examine which FA pathways (FA metabolism, β-oxidation, or ceramide metabolism) are critical to macrophage inflammation resolution response and find if the alteration in one pathway impacts the others. Aim 3 will explore the hypothesis that lipin-1 non-enzymatic activity promotes atherosclerotic regression and map the FA metabolic state of the regressing plaque. These proposed experiments will support the innova- tive idea that lipin-1 in macrophages is a dominant regulator of lipid channeling and promotes inflammation resolution by enhancing beta-oxidation while repressing ceramide synthesis. This application's beneficial impact will be the understanding that fatty acid metabolism is regulated to limit lipotoxicity and promote inflammation resolution to identify therapeutic targets to reduce the burden of atherosclerosis and its pathologic sequelae.