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Originally published In Press as doi:10.1194/jlr.M600417-JLR200 on February 1, 2007

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Journal of Lipid Research, Vol. 48, 1052-1061, May 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Functional LCAT deficiency in human apolipoprotein A-I transgenic, SR-BI knockout mice

Ji-Young Lee*, Robert M. Badeau*, Anny Mulya*, Elena Boudyguina*, Abraham K. Gebre*, Thomas L. Smith{dagger} and John S. Parks1,*

* Department of Pathology/Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157
{dagger} Department of Orthopedic Surgery, Wake Forest University School of Medicine, Winston-Salem, NC 27157

Published, JLR Papers in Press, February 1, 2007.

1 To whom correspondence should be addressed. e-mail: jparks{at}wfubmc.edu

Reduction of plasma LCAT activity has been observed in several conditions in which the size of HDL particles is increased; however, the mechanism of this reduction remains elusive. We investigated the plasma activity, mass, and in vivo catabolism of LCAT and its association with HDL particles in human apolipoprotein A-I transgenic, scavenger receptor class B type I knockout (hA-I Tg SR-BI–/–) mice. Compared with hA-I Tg mice, hA-I Tg SR-BI–/– mice had a 4-fold higher total plasma cholesterol concentration, which occurred predominantly in 13–18 nm diameter HDL particles, a significant reduction in plasma esterified cholesterol-total cholesterol (EC/TC) ratio, and significantly lower plasma LCAT activity, suggesting a decrease in LCAT protein. However, LCAT protein in plasma, hepatic mRNA for LCAT, and in vivo turnover of 35S-radiolabeled LCAT were similar in both genotypes of mice. HDL from hA-I Tg SR-BI–/– mice was enriched in sphingomyelin (SM), relative to phosphatidylcholine, and had less associated [35S]LCAT radiolabel and endogenous LCAT activity compared with HDL from hA-I Tg mice. We conclude that the decreased EC/TC ratio in the plasma of hA-I Tg SR-BI–/– mice is attributed to a reduction in LCAT reactivity with SM-enriched HDL particles.

Abbreviations: apoE, apolipoprotein E; CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; EC, esterified cholesterol; FC, free cholesterol; FPLC, fast-protein liquid chromatography; hA-I Tg, human apolipoprotein A-I transgenic; hrLCAT, human recombinant lecithin:cholesterol acyltransferase; PC, phosphatidylcholine; PLTP, phospholipid transfer protein; rHDL, recombinant high density lipoprotein; SM, sphingomyelin; SR-BI, scavenger receptor class B type I; TC, total cholesterol

Supplementary key words high density lipoproteins • cholesterol • sphingomyelin • lecithin:cholesterol acyltransferase • scavenger receptor class B type I


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