High levels of high density lipoprotein (HDL)-cholesterol are associated with lowered risk for cardiovascular disease. Although several mechanisms may play a role in HDL's protective effect, HDL and apolipoprotein-AI (apoAl), the major protein constituent of HDL, are major components of the reverse cholesterol transport pathway, in which cholesterol is removed from the periphery and transferred to the liver for excretion. In the first step of the reverse cholesterol transport pathway, apoAl acts as an acceptor for cell cholesterol and phospholipids via the cell membrane protein ABCAl, generating nascent HDL. Although this step in the pathway has been under intensive investigation, we still know very little about the molecular details of the ABCAl mediated assembly of cellular lipids on apoAI. Not all HDL is equivalent, and several studies have reported that individuals with coronary artery disease have HDL that is dysfunctional. We recently created an apoAl variant that is resistant to becoming dysfunctional. We propose to follow up on the mechanism of apoAl lipidation and reverse cholesterol transport in two specific aims.
Aim 1 will address mechanisms of both cell-free and cellular lipidation of apoAl using biophysical, biochemical, and genetic approaches.
Aim 2 will address the role of apoAl modification on in vivo reverse cholesterol transport and atherosclerosis lesion regression. We will explore the effects of inflammation on reverse cholesterol transport and apoAl modification, and we will determine if our novel apoAl variant is superior to wild type apoAl in mediating reverse cholesterol transport and lesion regression in several mouse models. In other words, we hope the discoveries we make will allow us to make "good cholesterol" even better.

Public Health Relevance

HDL is normally protective against atherosclerosis;however, HDL can become dysfunctional and lose its protective properties. The proposed studies will determine the efficacy of an oxidant resistant form of apoAl to prevent HDL dysfunction. These studies may lead to a better understanding of apoAl and HDL function, and provide preclinical evidence for the use of an oxidant resistant apoAl variant to treat atherosclerosis.

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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Cleveland Clinic Lerner
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Tang, W H Wilson; Wang, Zeneng; Shrestha, Kevin et al. (2015) Intestinal microbiota-dependent phosphatidylcholine metabolites, diastolic dysfunction, and adverse clinical outcomes in chronic systolic heart failure. J Card Fail 21:91-6
Grodin, Justin L; Hammadah, Muhammad; Fan, Yiying et al. (2015) Prognostic value of estimating functional capacity with the use of the duke activity status index in stable patients with chronic heart failure. J Card Fail 21:44-50
Grodin, Justin L; Neale, Sarah; Wu, Yuping et al. (2015) Prognostic comparison of different sensitivity cardiac troponin assays in stable heart failure. Am J Med 128:276-82
Tang, W H Wilson; Hazen, Stanley L (2014) The contributory role of gut microbiota in cardiovascular disease. J Clin Invest 124:4204-11
Hartiala, Jaana; Bennett, Brian J; Tang, W H Wilson et al. (2014) Comparative genome-wide association studies in mice and humans for trimethylamine N-oxide, a proatherogenic metabolite of choline and L-carnitine. Arterioscler Thromb Vasc Biol 34:1307-13
Shao, Zhili; Zhang, Renliang; Shrestha, Kevin et al. (2014) Usefulness of elevated urine neopterin levels in assessing cardiac dysfunction and exercise ventilation inefficiency in patients with chronic systolic heart failure. Am J Cardiol 113:1839-43
Brown, J Mark; Hazen, Stanley L (2014) Metaorganismal nutrient metabolism as a basis of cardiovascular disease. Curr Opin Lipidol 25:48-53
Duivenvoorden, Raphaƫl; Tang, Jun; Cormode, David P et al. (2014) A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation. Nat Commun 5:3065
Feig, Jonathan E; Hewing, Bernd; Smith, Jonathan D et al. (2014) High-density lipoprotein and atherosclerosis regression: evidence from preclinical and clinical studies. Circ Res 114:205-13
Brown, J Mark; Hazen, Stanley L (2014) Seeking a unique lipid signature predicting cardiovascular disease risk. Circulation 129:1799-803

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