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 i s 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 i s 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 i s 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.

Public Health Relevance

Crosstalk between metabolic and inflammatory signaling pathways plays an important role in metabolic diseases including atherosclerosis. We have uncovered new mechanisms involved linking metabolism and inflammation that may contribute to atherosclerosis. Further dissection of these pathways will provide insight into the pathogenesis of cardiovascular disease and may suggest new therapeutic approaches.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Los Angeles
United States
Zip Code
Yan, Xinmin; Lee, Sangderk; Gugiu, B Gabriel et al. (2014) Fatty acid epoxyisoprostane E2 stimulates an oxidative stress response in endothelial cells. Biochem Biophys Res Commun 444:69-74
Joo, Jong Wha J; Sul, Jae Hoon; Han, Buhm et al. (2014) Effectively identifying regulatory hotspots while capturing expression heterogeneity in gene expression studies. Genome Biol 15:r61
Mangul, Serghei; Caciula, Adrian; Al Seesi, Sahar et al. (2014) Transcriptome assembly and quantification from Ion Torrent RNA-Seq data. BMC Genomics 15 Suppl 5:S7
Albright, Jody; Quizon, Pamela M; Lusis, Aldons J et al. (2014) Genetic network identifies novel pathways contributing to atherosclerosis susceptibility in the innominate artery. BMC Med Genomics 7:51
Hormozdiari, Farhad; Kostem, Emrah; Kang, Eun Yong et al. (2014) Identifying causal variants at loci with multiple signals of association. Genetics 198:497-508
L├╝scher, Thomas F; Landmesser, Ulf; von Eckardstein, Arnold et al. (2014) High-density lipoprotein: vascular protective effects, dysfunction, and potential as therapeutic target. Circ Res 114:171-82
Jumabay, Medet; Abdmaulen, Raushan; Ly, Albert et al. (2014) Pluripotent stem cells derived from mouse and human white mature adipocytes. Stem Cells Transl Med 3:161-71
Ghazalpour, Anatole; Bennett, Brian J; Shih, Diana et al. (2014) Genetic regulation of mouse liver metabolite levels. Mol Syst Biol 10:730
Han, Buhm; Kang, Eun Yong; Raychaudhuri, Soumya et al. (2014) Fast pairwise IBD association testing in genome-wide association studies. Bioinformatics 30:206-13
Hasin-Brumshtein, Yehudit; Hormozdiari, Farhad; Martin, Lisa et al. (2014) Allele-specific expression and eQTL analysis in mouse adipose tissue. BMC Genomics 15:471

Showing the most recent 10 out of 638 publications