Project 1 will investigate the regulation of inflammation and lipid homeostasis in the context of macrophage foam cell formation and the pathogenesis of atherosclerosis. These studies will leverage our recent discovery that desmosterol, an intermediate in the cholesterol biosynthetic pathway, unexpectedly plays a key role in integration of the homeostatic response to excess cholesterol by activating LXR target genes required for cholesterol efflux, suppressing SREBP target genes involved in cholesterol and fatty acid biosynthesis, and inhibiting inflammatory responses by LXR-dependent and independent mechanisms. These findings have a number of unanticipated implications for understanding the pathophysiology of atherosclerosis and suggest new therapeutic approaches.
In Specific Aim 1, we will test the hypothesis that de-compensation of cholesterol homeostasis and 'expression of genes that amplify inflammatory responses in macrophage foam cells results from extrinsic, pro-inflammatory signals that are generated in the artery wall and induce TLR signaling.
In Specific Aim 2, we will test the hypothesis that in addition to serving as TLR-induced transcriptional activators of inflammatory-response genes, NFKB and IRF3 mediate TLR? dependent suppression of LXRs. Delineation of the mechanisms by which NFKB and IRF3 inhibit the lipid homeostatic and anti-inflammatory activities of LXRs may suggest new approaches for therapeutic intervention.
In Specific Aim 3, we will test the hypothesis that increasing endogenous levels of desmosterol or mimicking its activities will promote sterol excretion and inhibit the development of atherosclerosis. Conventional LXR ligands promote cholesterol efflux and inhibit atherosclerosis in mice, but are not useful drugs because they induce the expression of SREBP1c and cause marked hypertriglyceridemia. In contrast, desmosterol activates LXRs but suppresses SREBP processing. In this aim, we will investigate whether treatment with a putative desmosterol mimetic or raising endogenous desmosterol levels can be used as approaches to restore cholesterol homeostasis in lesion macrophages without causing adverse effects on circulating lipoprotein levels.

Public Health Relevance

Atherosclerosis remains a major cause of morbidity and mortality in industrialized societies. Although reduction of circulating cholesterol levels is an effective therapeutic strategy, not all patients at risk for disease respond to existing drugs. The proposed studies investigate new pathways and molecular mechanisms underlying the pathogenesis of atherosclerosis that could potentially be targeted for therapeutic intervention.

National Institute of Health (NIH)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
La Jolla
United States
Zip Code
Fan, Weiwei; Evans, Ronald (2015) PPARs and ERRs: molecular mediators of mitochondrial metabolism. Curr Opin Cell Biol 33:49-54
Tsimikas, Sotirios; Duff, Gordon W; Berger, Peter B et al. (2014) Pro-inflammatory interleukin-1 genotypes potentiate the risk of coronary artery disease and cardiovascular events mediated by oxidized phospholipids and lipoprotein(a). J Am Coll Cardiol 63:1724-34
Gonen, Ayelet; Hansen, Lotte F; Turner, William W et al. (2014) Atheroprotective immunization with malondialdehyde-modified LDL is hapten specific and dependent on advanced MDA adducts: implications for development of an atheroprotective vaccine. J Lipid Res 55:2137-55
Baldan, Angel; Gonen, Ayelet; Choung, Christina et al. (2014) ABCG1 is required for pulmonary B-1 B cell and natural antibody homeostasis. J Immunol 193:5637-48
Daniel, Bence; Nagy, Gergely; Hah, Nasun et al. (2014) The active enhancer network operated by liganded RXR supports angiogenic activity in macrophages. Genes Dev 28:1562-77
Hilgendorf, Ingo; Theurl, Igor; Gerhardt, Louisa M S et al. (2014) Innate response activator B cells aggravate atherosclerosis by stimulating T helper-1 adaptive immunity. Circulation 129:1677-87
d'Uscio, Livius V; He, Tongrong; Santhanam, Anantha Vijay R et al. (2014) Mechanisms of vascular dysfunction in mice with endothelium-specific deletion of the PPAR-? gene. Am J Physiol Heart Circ Physiol 306:H1001-10
Hong, Suk-Hyun; Ahmadian, Maryam; Yu, Ruth T et al. (2014) Nuclear receptors and metabolism: from feast to famine. Diabetologia 57:860-7
Suh, Jae Myoung; Jonker, Johan W; Ahmadian, Maryam et al. (2014) Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer. Nature 513:436-9
Zhao, Xuan; Cho, Han; Yu, Ruth T et al. (2014) Nuclear receptors rock around the clock. EMBO Rep 15:518-28

Showing the most recent 10 out of 51 publications