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Journal of Lipid Research, Vol. 45, 337-346, February 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

In vivo modulation of HDL phospholipid has opposing effects on SR-BI- and ABCA1-mediated cholesterol efflux

Patricia G. Yancey^*, Masa-aki Kawashiri, Ryan Moore, Jane M. Glick, David L. Williams^**, Margery A. Connelly^**, Daniel J. Rader and George H. Rothblat^1,*

^* Division of Gastroenterology and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104
Departments of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
^** Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY 11794

¹ To whom correspondence should be addressed. e-mail: rothblat{at}email.chop.edu

The effects of in vivo modulation of HDL phospholipid (PL) on scavenger receptor class BI (SR-BI)- and ATP binding cassette transporter 1 (ABCA1)-mediated efflux were examined by overexpressing either endothelial lipase (EL) or phosphatidylserine phospholipase (PS-PLA₁) in human apolipoprotein A-I (apoA-I) transgenic mice. Overexpression of EL led to large reductions in the serum PL/apoA-I ratio (-60%), total cholesterol (TC; -89%), and HDL cholesterol (-91%). Relative to the serum before overexpression of EL, the efflux potential of the serum via SR-BI decreased by 90% and ABCA1-mediated efflux increased by 63%. In contrast to overexpression of EL, overexpression of PS-PLA₁ led to increases in the PL/apoA-I ratio (88%), TC (78%), HDL cholesterol (57%), and HDL size. The efflux potential of the serum increased by 60% via SR-BI and decreased by 57% via ABCA1. There were significant positive correlations between SR-BI-mediated efflux and a number of serum parameters, including PL/apoA-I ratio, PL, TC, free cholesterol (FC), and HDL cholesterol. In striking contrast, the same correlations were seen with ABCA1-mediated efflux, but the relationships were inverse.

In summary, in vivo modulation of HDL PL content affects ABCA1- and SR-BI-mediated efflux in a reciprocal manner. These findings indicate that the type of lipase acting on HDL in vivo will determine which FC efflux pathway the HDL serves. Additionally, the extent of lipolysis will determine the efficiency of FC removal via this pathway.

Abbreviations: ABCA1, ATP binding cassette transporter 1; EL, endothelial lipase; PS-PLA₁, phosphatidylserine phospholipase; SR-BI, scavenger receptor class BI

Supplementary key words high density lipoprotein • scavenger receptor BI • ATP binding cassette transporter 1

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