Our long-term goal is to understand how lipids regulate gene expression in vascular cells, and how these pathways contribute to the pathogenesis of coronary artery disease. Epidemiologic studies have clearly established the pathogenic link between dyslipidemias, such as hypercholesterolemia and hypertriglyceridemia, and the development of atherosclerotic heart disease. Intensive research in understanding the biochemical modifications that confer pathogenicity to the LDL particles has elucidated the molecular route through which oxLDL regulates gene expression in lesional macrophages and contributes to the development of vascular disease. However, the molecular and cellular responses to triglyceride-rich lipoproteins, such as VLDL, remain poorly understood. Our previous studies have identified a transcriptional pathway in macrophages that is driven by VLDL through the activation of PPAR delta. Interestingly, these studies revealed that the fatty acids that are present in VLDL particle can potently transactivate the PPAR delta receptor. Consistent with this, treatment of wild type, but not PPAR delta null, macrophages with the VLDL particle resulted in transcriptional induction of target genes. The studies proposed in the present grant application will take molecular, cellular, and genetic approaches to further investigate how PPAR gamma and delta orchestrate the macrophage response to incoming fatty acids. Data from these studies will greatly enhance our understanding of the how these receptors regulate macrophage homeostatic responses in both physiologic and pathophysiologic conditions, and potentially lead to the identification of new therapeutic targets to treat this chronic disease.
The specific aims of this proposal are to: 1) Determine the pathways by which PPAR gamma controls macrophage fatty acid metabolism, 2) Assess the regulatory role of PPAR delta in the utilization of fatty acids by macrophages, and 3) Determine the molecular mechanisms by which PPAR delta regulates macrophage inflammatory response.
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