Accelerated atherosclerosis displays a complex pathogenesis including alterations in lipids, inflammatory state involving the immune system. HDL apoA-I protects against these changes mainly through its ability to organize and recruit cholesterol and oxygenated forms of cholesterol and phospholipids from immune cells protecting them from dysregulation and apoptosis. In the current proposal, we will investigate the molecular mechanisms responsible for immune cell cholesterol deposition, accelerated atherosclerosis and the development of an autoimmune phenotype in response to an atherogenic diet in LDL receptor, apoA-Idouble knockout (DKO) mice. In previous studies, when DKO and LDLr-/- (SKO) mice were fed an atherogenic diet, DKO mice developed enlarged peripheral lymph nodes (LNs) and spleens compared to SKO mice. DKO LN were enriched in cholesterol ester (CE) and contained expanded populations of CE enriched T, B, dendritic cells and macrophages. Plasma antibodies to dsDNA and oxidized LDL were also increased in DKO suggesting an autoimmune phenotype. Both LN enlargement and LN CE accumulation were """"""""prevented"""""""" when diet-fed DKO mice were treated with apoA-I at the time the diet was initiated. Regardless of the level of dietary cholesterol, DKO mice consistently showed lower plasma cholesterol than SKO mice, yet greater aortic cholesterol deposition and inflammation. Therefore, the goal of this proposal is to use the DKO mouse to investigate the mechanisms by which apoA-I 1) modulates CE and oxysterol accumulation and activation in lymphocytes, 2) alters the proliferation and/or apoptosis of CE loaded lymphocytes, 3) affects the contribution of T cells and DC to plaque infiltration in both progression and regression of atherosclerosis in diet-fed DKO mice.
Atherosclerosis is a chronic inflammatory disease that is initiated by cellular cholesterol dysregulation at the vessel wall. Our proposed studies will investigate the mechanisms explaining the role of apoA-I in regulating lymphocyte cholesterol homeostasis, autoimmunity and atherosclerosis. These studies will likely provide new targets for therapeutic interventions to control the inflammatory processes that exacerbate atherosclerosis.
|Pollard, Ricquita D; Fulp, Brian; Sorci-Thomas, Mary G et al. (2016) High-Density Lipoprotein Biogenesis: Defining the Domains Involved in Human Apolipoprotein A-I Lipidation. Biochemistry 55:4971-81|
|Liu, Mingxia; Seo, Jeongmin; Allegood, Jeremy et al. (2014) Hepatic apolipoprotein M (apoM) overexpression stimulates formation of larger apoM/sphingosine 1-phosphate-enriched plasma high density lipoprotein. J Biol Chem 289:2801-14|
|Sorci-Thomas, Mary G; Thomas, Michael J (2013) Why targeting HDL should work as a therapeutic tool, but has not. J Cardiovasc Pharmacol 62:239-46|
|Pollard, Ricquita D; Fulp, Brian; Samuel, Michael P et al. (2013) The conformation of lipid-free human apolipoprotein A-I in solution. Biochemistry 52:9470-81|
|Martel, Catherine; Li, Wenjun; Fulp, Brian et al. (2013) Lymphatic vasculature mediates macrophage reverse cholesterol transport in mice. J Clin Invest 123:1571-9|
|Sorci-Thomas, Mary G; Zabalawi, Manal; Bharadwaj, Manish S et al. (2012) Dysfunctional HDL containing L159R ApoA-I leads to exacerbation of atherosclerosis in hyperlipidemic mice. Biochim Biophys Acta 1821:502-12|
|Sorci-Thomas, Mary G; Thomas, Michael J (2012) High density lipoprotein biogenesis, cholesterol efflux, and immune cell function. Arterioscler Thromb Vasc Biol 32:2561-5|
|Sorci-Thomas, Mary G; Owen, John S; Fulp, Brian et al. (2012) Nascent high density lipoproteins formed by ABCA1 resemble lipid rafts and are structurally organized by three apoA-I monomers. J Lipid Res 53:1890-909|
|Potteaux, Stephane; Gautier, Emmanuel L; Hutchison, Susan B et al. (2011) Suppressed monocyte recruitment drives macrophage removal from atherosclerotic plaques of Apoe-/- mice during disease regression. J Clin Invest 121:2025-36|
|Wang, Weiling; Xu, Hao; Shi, Yang et al. (2010) Genetic deletion of apolipoprotein A-I increases airway hyperresponsiveness, inflammation, and collagen deposition in the lung. J Lipid Res 51:2560-70|
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