Macrophage- associated lipin-1 lipid synthesis regulates foam cell inflammatory responses

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The proposed research application seeks a better understanding of the underpinnings of foam cell inflammatory responses that promote atheroma formation, plaque progression, and ultimately plaque instability leading to catastrophic cardiovascular disease (CVD). Hypercholesterolemia results in the formation of modified low den- sity lipoproteins (modLDL) in the arterial intima causing atherosclerosis. ModLDLs elicit a pro-inflammatory re- sponse from macrophages that drives atherosclerosis, leading to catastrophic CVD. The goal of my laboratory is to elucidate the mechanisms that mediate modLDL-elicited inflammatory responses, as this understanding may allow us to better treat CVD than current therapies which only reduce CVD by 30%. The lipid-laden pheno- type that is characteristic of macrophage foam cells is due to lipid droplet biogenesis. Lipid droplet biogenesis requires glycerolipid synthesis, however glycerolipid synthesis in and of itself is not thought to contribute to foam cell inflammatory responses. During glycerolipid synthesis, lipin-1 converts phosphatidate to diglyceride as the penultimate step of lipid droplet generation. My laboratory has demonstrated for the first time that lipin-1 directly contributes to the modLDL-elicited pro-inflammatory state of macrophages, suggesting that glycerolipid synthe- sis may contribute to atherosclerosis inflammation. The objective of this proposal is to define the mechanism by which lipin-1 regulates the modLDL-elicited pro-inflammatory responses that contribute to atherosclerosis. Our central hypothesis is that modLDL induces lipin-1 enzymatic activity as part of glycerolipid synthesis, causing sustained activation of a signaling axis responsible for modLDL-elicited pro-inflammatory responses that promote atherosclerosis. We will test our central hypothesis and accomplish the objective of this application by pursuing three specific aims: 1) Understanding how lipin-1 enzymatic activity regulates modLDL-elicited diglyceride pro- duction and diglyceride mediated responses in macrophages. 2) Determine if lipin-1 mediates modLDL-loaded macrophage hyper-responsiveness. 3) Define the extent to which lipin-1 in myeloid cells promotes atheroscle- rosis. In aims 1 and 2, we propose to genetically restore lipin-1 enzymatic activity in bone marrow-derived mac- rophages from our newly developed mouse that lacks lipin-1 enzymatic activity from myeloid cells only. We will examine the physiological outcome of diglyceride-dependent signaling, cJun activity, and pro-inflammatory re- sponses. During aim 3 we will use our novel mouse in which lipin-1 enzymatic activity is lacking in myeloid cells and we will monitor atherosclerotic progression and plaque inflammation using the LDL receptor knockout (LDLR- /-) and AAV8-PCSK9D377Y models of atherosclerosis. These proposed experiments will provide support to the innovative idea that lipin-1 enzymatic activity, as part of glycerolipid synthesis in macrophages, is a key contrib- utor to inflammation that drives atherosclerotic progression. This work is significant as it may result in the future development of pharmacological strategies that modulate glycerolipid synthesis in foam cells to reduce athero- sclerotic inflammation without causing systemic immunosuppression, thus reducing CVD burden.