The overall goal of this proposal is to study the interactions of triglyceride-rich lipoproteins(TGRL), lipolysis of TGRL, and HDL with the artery wall.
The aims of this proposal are:
Aim 1. Test the hypothesis that lipolysis of TGRL increases the accumulation of both surface and core lipid components of TGRL in the artery wall as a result of an increase in endothelial layer permeability. We will determine before and after lipolysis: (1) endothelial layer permeability to fluorescently labeled dextran, (2) accumulation of TGRL remnant particles, and (3) localization of TGRL surface and core lipid in atherosclerotic and nonatherosclerotic mouse carotid arteries.
Aim 2. Test the hypotheses that (a) HDL accepts lipolysis products that injure endothelium and thus reduces endothelial layer permeability. (b) HDL removes lipid from the artery wall derived from lipolysis of TGRL. We will (1) measure permeability to dextran following lipolysis in the presence and absence of HDL, and (2) load the vessel wall with fluorescently labeled lipolysis products and measure their removal by HDL.
Aim 3. Test the hypothesis that apoE derived from arterial macrophages competitively inhibits binding of apoE-associated lipoproteins to glycosaminoglycans, thereby reducing lipoprotein retention in the artery wall. We will use apoE-deficient mice to determine the vascular retention of fluorescently labeled lipid emulsions (1) with and without associated apoE, and (2) in the presence and absence of macrophage-derived apoE following bone marrow or aortic transplantation. Further studies are needed to investigate the interactions of lipoproteins with the artery wall comprehensively and precisely. Using new approaches, our research will define mechanisms of TGRL-mediated flux in the artery wall and atherosclerosis formation and prevention. Our work will provide insight into the pathophysiology of atherosclerosis in patients with hypertriglyceridemia.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular and Renal Study Section (CVB)
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University of California Davis
Internal Medicine/Medicine
Schools of Medicine
United States
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Aung, Hnin Hnin; Altman, Robin; Nyunt, Tun et al. (2016) Lipotoxic brain microvascular injury is mediated by activating transcription factor 3-dependent inflammatory and oxidative stress pathways. J Lipid Res 57:955-68
Eiselein, Larissa; Nyunt, Tun; Lamé, Michael W et al. (2015) TGRL Lipolysis Products Induce Stress Protein ATF3 via the TGF-? Receptor Pathway in Human Aortic Endothelial Cells. PLoS One 10:e0145523
Aung, Hnin H; Tsoukalas, Athanasios; Rutledge, John C et al. (2014) A systems biology analysis of brain microvascular endothelial cell lipotoxicity. BMC Syst Biol 8:80
Yahiatène, Idir; Aung, Hnin H; Wilson, Dennis W et al. (2014) Single-molecule quantification of lipotoxic expression of activating transcription factor 3. Phys Chem Chem Phys 16:21595-21601
den Hartigh, Laura J; Altman, Robin; Norman, Jennifer E et al. (2014) Postprandial VLDL lipolysis products increase monocyte adhesion and lipid droplet formation via activation of ERK2 and NF?B. Am J Physiol Heart Circ Physiol 306:H109-20
Armstrong, Ehrin J; Rutledge, John C; Rogers, Jason H (2013) Coronary artery revascularization in patients with diabetes mellitus. Circulation 128:1675-85
Aung, Hnin H; Lame, Michael W; Gohil, Kishorchandra et al. (2013) Induction of ATF3 gene network by triglyceride-rich lipoprotein lipolysis products increases vascular apoptosis and inflammation. Arterioscler Thromb Vasc Biol 33:2088-96
den Hartigh, Laura J; Altman, Robin; Hutchinson, Romobia et al. (2012) Postprandial apoE isoform and conformational changes associated with VLDL lipolysis products modulate monocyte inflammation. PLoS One 7:e50513
Ng, Kit Fai; Aung, Hnin Hnin; Rutledge, John C (2011) Role of triglyceride-rich lipoproteins in renal injury. Contrib Nephrol 170:165-71
Schie, Iwan W; Wu, Jian; Weeks, Tyler et al. (2011) Label-free imaging and analysis of the effects of lipolysis products on primary hepatocytes. J Biophotonics 4:425-34

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