Selective delipidation of plasma HDL enhances reverse cholesterol transport in vivo

Frank M. Sacks¹^,*^,, Lawrence L. Rudel, Adam Conner, Hassibullah Akeefe, Gerhard Kostner^**, Talal Baki, George Rothblat, Margarita de la Llera-Moya, Bela Asztalos, Timothy Perlman, Chunyu Zheng^*^,, Petar Alaupovic^***, Jo-Ann B. Maltais and H. Bryan Brewer^,

^* Harvard School of Public Health and Harvard Medical School, Boston, MA
Wake Forest University Health Sciences, Winston-Salem, NC
Lipid Sciences Incorporated, Pleasanton, CA
^** Medical University of Graz, Graz, Austria
Children's Hospital of Philadelphia, Philadelphia, PA
Tufts University, Boston, MA
^*** Oklahoma Medical Research Foundation, Oklahoma City, OK
Medstar Research Institute, Washington Hospital Center, Washington, DC

The research was conducted at Lipid Sciences (Adam Conner, HassibulahAkeefe, Timothy Perlman, Dr. Maltais); and at Wake Forest University(Drs. Rudel and Baki), University of Graz (Dr. Kostner), Children'sHospital of Philadelphia (Drs. Rothblat and de la Llera-Moya),Tufts University (Dr. Asztalos), and Oklahoma Medical ResearchFoundation (Dr. Alaupovic), funded by grants from Lipid Sciences.The monkey atherosclerosis progression study was funded by aNational Institutes of Health grant to LLR, HL-24736.

Published, JLR Papers in Press, January 14, 2009.

^¹ To whom correspondence should be addressed. e-mail: fsacks{at}hsph.harvard.edu

Uptake of cholesterol from peripheral cells by nascent smallHDL circulating in plasma is necessary to prevent atherosclerosis.This process, termed reverse cholesterol transport, produceslarger cholesterol-rich HDL that transfers its cholesterol tothe liver facilitating excretion. Most HDL in plasma is cholesterol-rich.We demonstrate that treating plasma with a novel selective delipidationprocedure converts large to small HDL [HDL-selectively delipidated(HDL-sdl)]. HDL-sdl contains several cholesterol-depleted speciesresembling small ${alpha}$ , preβ-1, and other preβ forms. Selectivedelipidation markedly increases efficacy of plasma to stimulateABCA1-mediated cholesterol transfer from monocytic cells toHDL. Plasma from African Green monkeys underwent selective HDLdelipidation. The delipidated plasma was reinfused into fivemonkeys. Preβ-1-like HDL had a plasma residence time of8 ± 6 h and was converted entirely to large ${alpha}$ -HDL havingresidence times of 13–14 h. Small ${alpha}$ -HDL was converted entirelyto large ${alpha}$ -HDL. These findings suggest that selective HDL delipidationactivates reverse cholesterol transport, in vivo and in vitro.Treatment with delipidated plasma tended to reduce diet-inducedaortic atherosclerosis in monkeys measured by intravascularultrasound. These findings link the conversion of small to largeHDL, in vivo, to improvement in atherosclerosis.

Supplementary key words apolipoprotein A-I • kinetics • lipoproteins • nonhuman primates • ABCA1 • SRB1 • preβ-1

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