Coronary Heart Disease is the leading cause of death in our society. Underlying this disease is the pathologic process known as atherosclerosis. The central theme of this Program is to define aspects of lipoprotein metabolism important in atherogenesis. Atherosclerosis occurs when plasma low density lipoproteins (LDL) get deposited in the artery wall. Atherosclerotic lesions rich in cholesteryl esters develop in response to LDL deposition. Studies in this program project will help define how LDL precursor lipoproteins are actually made inside cells (Project 2), how concentrations are controlled, and properties of LDL that make them more atherogenic. We have identified an enzyme in the liver and intestine, termed ACAT2, that appears to be important in this context, and we will use genetically engineered mice that no longer have this enzyme to show how this enzyme alters cholesterol metabolism in the liver and in the intestine (Project 1). We will test the hypothesis that cholesteryl oleate accumulation in plasma as LDL promotes atherosclerosis, and we will attempt studies to determine if we can identify cholesteryl oleate as a biomarker for ACAT2 in humans. High density lipoproteins (HDL) are the class of lipoproteins that help remove cholesterol from arteries. We will do studies to help determine how HDL particles are made. We know that the principal protein of HDL, called apoA-l, is secreted without lipid into plasma and then assembles lipid after interaction on the surface of cells with a transporter termed ABCA1 found mostly in the liver. Factors influencing this interaction will be measured (Project 3). Further, the properties of the major protein of HDL, termed apoA-l, which are responsible for its efficient function in lipid assimilation and transport will be assessed in Project 4. Important characteristics of the protein will be identified through the study of natural mutations of the protein using techniques to define protein structure. In all of these projects, genetically engineered mice will provide specific insights into molecular physiology. Overall, this program project will provide basic information that will help us understand the role of lipoprotein metabolism in atherosclerosis so that prevention of CHD can be more readily achieved.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Ershow, Abby
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Wake Forest University Health Sciences
Schools of Medicine
United States
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Zhang, Jun; Sawyer, Janet K; Marshall, Stephanie M et al. (2014) Cholesterol esters (CE) derived from hepatic sterol O-acyltransferase 2 (SOAT2) are associated with more atherosclerosis than CE from intestinal SOAT2. Circ Res 115:826-33
Chung, Soonkyu; Cuffe, Helen; Marshall, Stephanie M et al. (2014) Dietary cholesterol promotes adipocyte hypertrophy and adipose tissue inflammation in visceral, but not in subcutaneous, fat in monkeys. Arterioscler Thromb Vasc Biol 34:1880-7
Medina, Marisa W; Bauzon, Frederick; Naidoo, Devesh et al. (2014) Transmembrane protein 55B is a novel regulator of cellular cholesterol metabolism. Arterioscler Thromb Vasc Biol 34:1917-23
Bi, Xin; Zhu, Xuewei; Gao, Chuan et al. (2014) Myeloid cell-specific ATP-binding cassette transporter A1 deletion has minimal impact on atherogenesis in atherogenic diet-fed low-density lipoprotein receptor knockout mice. Arterioscler Thromb Vasc Biol 34:1888-99
Marshall, Stephanie M; Gromovsky, Anthony D; Kelley, Kathryn L et al. (2014) Acute sterol o-acyltransferase 2 (SOAT2) knockdown rapidly mobilizes hepatic cholesterol for fecal excretion. PLoS One 9:e98953
Cao, Qiang; Rong, Shunxing; Repa, Joyce J et al. (2014) Histone deacetylase 9 represses cholesterol efflux and alternatively activated macrophages in atherosclerosis development. Arterioscler Thromb Vasc Biol 34:1871-9
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
Marshall, Stephanie M; Kelley, Kathryn L; Davis, Matthew A et al. (2014) Reduction of VLDL secretion decreases cholesterol excretion in niemann-pick C1-like 1 hepatic transgenic mice. PLoS One 9:e84418
Bi, Xin; Zhu, Xuewei; Duong, MyNgan et al. (2013) Liver ABCA1 deletion in LDLrKO mice does not impair macrophage reverse cholesterol transport or exacerbate atherogenesis. Arterioscler Thromb Vasc Biol 33:2288-96
Melchior, John T; Sawyer, Janet K; Kelley, Kathryn L et al. (2013) LDL particle core enrichment in cholesteryl oleate increases proteoglycan binding and promotes atherosclerosis. J Lipid Res 54:2495-503

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