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Journal of Lipid Research, Vol. 45, 1724-1732, September 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

SR-BI- and ABCA1-mediated cholesterol efflux to serum from patients with Alagille syndrome

Patricia G. Yancey^*, Bela F. Asztalos, Nicolas Stettler^*, David Piccoli^*, David L. Williams, Margery A. Connelly and George H. Rothblat^1,*

^* Division of Gastroenterology and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104
Lipid Metabolism Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center, Tufts University, Boston, MA 02111
Department of Pharmacological Sciences, State University of New York, Stony Brook, NY 11794

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

Alagille syndrome is associated with bile duct paucity resulting in liver disease. Patients can be divided into mildly and severely icteric groups, with both groups having altered lipoproteins. The incidence of ischemic heart disease is rare in severely cholestatic children despite increased total cholesterol and decreased high density lipoprotein cholesterol (HDL-C). The present studies examine the impact of altered lipid and lipoproteins on scavenger receptor class B type I (SR-BI)- and ABCA1-mediated efflux to serum from both groups. Efflux was compared with serum from 29 patients (15 with normal plasma cholesteryl ester, 14 with low cholesteryl ester). Efflux via SR-BI and ABCA1 was studied using cell systems having either low or high expression levels of these receptors. SR-BI efflux was lower (P = 0.04) with serum from severely icteric patients (3.9 ± 1.4%) compared with serum from mildly icteric patients (5.1 ± 1.4%) and was positively correlated with HDL-C and its apolipoproteins. SR-BI-mediated efflux was not correlated with any particular mature HDL but was negatively correlated with small lipid-poor preß-1 HDL. Consistent with severely icteric patients having high preß-1 HDL levels, the ABCA1 efflux was significantly higher with their serum (4.8 ± 2.2%) compared with serum from mildly icteric patients (2.0 ± 0.6%) and was positively correlated with preß-1 HDL.

These studies demonstrated that preß-1 HDL is the preferred acceptor for ABCA1 efflux, whereas many particles mediate SR-BI efflux.

Abbreviations: apoB, apolipoprotein B; CE, cholesteryl ester; cpt, 8-(4-chlorophenylthio)-adenosine 3':5'-cyclic monophosphate; CS, calf serum; FC, free cholesterol; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; LpX, lipoprotein X; LSC, liquid scintillation counting; PL, phospholipid; SR-BI, scavenger receptor class B type I; TC, total cholesterol; TG, triglyceride

Supplementary key words high density lipoprotein • scavenger receptor class B type I • ATP binding cassette transporter 1

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