Regulation of Lipid Metabolism and Inflammation by the Orphan Nuclear Receptors

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A long-term goal of our laboratory is to understand the role that lipid-activated transcription factors play in the coordination of metabolic and inflammatory gene expression in human disease. Work accomplished in the current grant period delineated new functions for LXR and NR4A nuclear receptors in the control of cholesterol and glucose metabolism and also revealed unexpected roles for these factors in immune responses. In the next funding period we propose to extend prior work to address the function of LXR in metabolic-immune crosstalk on three levels: innate immune responses, acquired immune functions, and crosstalk between the innate and acquired immune systems. We further propose to build upon our discovery of the importance of NR4A nuclear receptors in the transcriptional control of both inflammation and metabolism. Collectively, these studies are expected to advance our understanding of the molecular pathways that integrate metabolic and inflammatory processes in physiology and disease. Our first aim is to test the hypothesis that metabolic activation of IRF3 signaling regulates LXR function and cholesterol metabolism. We will explore the impact of lipid mediators on IRF3 signaling and test the influence of IRF3- LXR crosstalk on the development of atherosclerosis. Our second aim is to test the hypothesis that lipiddependent LXR signaling is a physiologic modulator of lymphocyte function. We will determine mechanisms whereby cholesterol metabolism and LXR signaling regulate adaptive immune responses and the development of lymphocyte-dependent inflammatory diseases. We will also define the mechanistic basis for the immunomodulatory effects of synthetic LXR agonists. Our third aim is to define the impact of macrophage NR4A receptors on inflammation and the development of atherosclerosis using gain- and lossof- fucntion mouse models. We will test the involvement of NR4A receptors in crosstalk between inflammatory and metabolic signaling and determine the mechanisms underlying such crosstalk. Completion of these aims is expected to bring new insight into fundamental mechanisms underlying metabolism and inflammation and may suggest new opportunities for therapeutic intervention in cardiovascular disease.