Submitted on September 21, 2006
Revised on January 31, 2007
Accepted on January 31, 2007
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, and John S. Parks
Pathology/Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157
Corresponding Author: 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 ca-tabolism of LCAT and its association with HDL particles in human apoA-I transgenic, SR-BI 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 to total cholesterol (EC/TC) ratio, and a 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 (PC), 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.
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