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.
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.
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