The objective of this project is to define novel molecular mechanisms by which nuclear receptors modulate lipid and inflammatory homeostasis. Given the central roles that metabolism and inflammation play in diseases such as diabetes and atherosclerosis, elucidating novel lipid and immune signaling pathways may uncover new opportunities for therapeutic intervention, and will advance our understanding of fundamental physiological and pathophysiological processes. Work from our group and others over the past 10 years has characterized the oxysterol-activated nuclear receptor LXR as a major regulator of cholesterol and fatty acid homeostasis that modulates the development of metabolic disease. However, the impact of LXRs on the major constituents of membranes-phospholipids-has not been rigorously investigated. We have discovered that LXRs dynamically remodel membrane phospholipids in response to metabolic signals through transcriptional induction of the gene encoding the enzyme lysophosphatidylcholine acyltransferase 3 (Lpcat3). Building on this preliminary work, we propose a series of molecular, cell biological and mouse studies to investigate new hypotheses regarding the roles of LXR and membrane phospholipid composition in the control of lipid metabolism and inflammation.
Specific Aim 1 is to elucidate the role of Lpcat3-dependent phospholipid remodeling in hepatic lipid metabolism.
Specific Aim 2 is to define the role of Lpcat3 in intestinal lipid metabolism.
Specific Aim 3 is to determine th role of the LXR-Lpcat3 pathway in inflammation. Dissecting the molecular pathways that control lipid metabolism and inflammatory responses has important implications for metabolic disease.
Lipid metabolism and liver X receptor signaling are important determinants of metabolic diseases including diabetes and atherosclerosis. Elucidating novel lipid signaling pathways regulated by liver X receptors may uncover new opportunities for therapeutic intervention, and will advance our understanding of fundamental physiological and pathophysiological processes. The discovery that LXR regulates phospholipid metabolism identifies a new mechanism for the regulation of metabolism and inflammation in human disease.
