The incidence of premature coronary atherosclerosis in the human population is highly correlated to decreased concentrations of plasma high density lipoproteins (HDL) and its major apoprotein, apolipoprotein A-I (apo A-I). Transgenic and knockout mouse studies have shown that circulating HDL apo A-I primarily plays a """"""""protective function"""""""" in response to high levels of atherogenic lipoproteins through its ability to accept, organize and transport cholesterol out of the artery to the liver for uptake and excretion into bile. This """"""""reverse cholesterol transport pathway"""""""" is highly dependent upon apo A-I's ester conversion in the plasma. Blockage or reduction in apo A-I's ability to carry out this function can lead to reduced reverse cholesterol transport and inefficient removal of peripheral tissue cholesterol. Data from the applicants' laboratory show that structural alterations in the conformation of plasma apo A-I can have a more profound effect on HDL apo A-I formation and maturation than merely the absence of native apo A-I alone. Their studies show that LCAT activation and thus, plasma cholesterol esterification is inhibited by the presence of a mutant form of apo A-I in plasma. The mutant apo A-I does this by inhibiting plasma cholesterol esterification even in plasma containing native or wild type apo A-I. Thus, they propose to investigate the molecular and cellular basis for the severe disruption in HDL metabolism resulting from the hepatic expression of the mutant human apo A-I, termed 6 apo A-I. This mutant of apo A-I lacks repeat 6, a single proline punctuated 22-mer and has been shown to have a similar plasma lipoprotein phenotype to a known human apo A-I mutation, called apo A-I. In a newly created transgenic mouse model, designated Tg6 apo A-I the applicants propose to conduct dietary-cholesterol feeding studies to determine if mutant apo A-I protects against atherosclerosis in mice with hypercholesterolemia. They also plan to elucidate the molecular and cellular basis for 6 apo A-I's disruption of HDL apo A-I metabolism.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064163-04
Application #
6642190
Study Section
Metabolism Study Section (MET)
Program Officer
Applebaum-Bowden, Deborah
Project Start
2000-09-15
Project End
2005-05-14
Budget Start
2003-08-01
Budget End
2005-05-14
Support Year
4
Fiscal Year
2003
Total Cost
$324,000
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Pathology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
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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