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)
Project #
Application #
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cleveland Clinic Lerner
United States
Zip Code
Hammadah, Muhammad; Brennan, Marie-Luise; Wu, Yuping et al. (2016) Usefulness of Relative Hypochromia in Risk Stratification for Nonanemic Patients With Chronic Heart Failure. Am J Cardiol 117:1299-304
Senthong, Vichai; Li, Xinmin S; Hudec, Timothy et al. (2016) Plasma Trimethylamine N-Oxide, a Gut Microbe-Generated Phosphatidylcholine Metabolite, Is Associated With Atherosclerotic Burden. J Am Coll Cardiol 67:2620-8
Gulshan, Kailash; Brubaker, Gregory; Conger, Heather et al. (2016) PI(4,5)P2 Is Translocated by ABCA1 to the Cell Surface Where It Mediates Apolipoprotein A1 Binding and Nascent HDL Assembly. Circ Res 119:827-38
Iqbal, Asif J; Barrett, Tessa J; Taylor, Lewis et al. (2016) Acute exposure to apolipoprotein A1 inhibits macrophage chemotaxis in vitro and monocyte recruitment in vivo. Elife 5:
Iqbal, Asif J; Fisher, Edward A; Greaves, David R (2016) Inflammation-a Critical Appreciation of the Role of Myeloid Cells. Microbiol Spectr 4:
Hammadah, Muhammad; Georgiopoulou, Vasiliki V; Kalogeropoulos, Andreas P et al. (2016) Elevated Soluble Fms-Like Tyrosine Kinase-1 and Placental-Like Growth Factor Levels Are Associated With Development and Mortality Risk in Heart Failure. Circ Heart Fail 9:e002115
Fisher, Edward A (2016) Regression of Atherosclerosis: The Journey From the Liver to the Plaque and Back. Arterioscler Thromb Vasc Biol 36:226-35
Zhu, Weifei; Gregory, Jill C; Org, Elin et al. (2016) Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk. Cell 165:111-24
Grodin, Justin L; Verbrugge, Frederik H; Ellis, Stephen G et al. (2016) Importance of Abnormal Chloride Homeostasis in Stable Chronic Heart Failure. Circ Heart Fail 9:e002453
Hartiala, Jaana A; Tang, W H Wilson; Wang, Zeneng et al. (2016) Genome-wide association study and targeted metabolomics identifies sex-specific association of CPS1 with coronary artery disease. Nat Commun 7:10558

Showing the most recent 10 out of 134 publications