Abstract
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-ITg SR-BI-/-) mice. Compared with hA-ITg mice, hA-ITg 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-ITg 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-ITg mice. We conclude that the decreased EC/TC ratio in the plasma of hA-ITg SR-BI-/- mice is attributed to a reduction in LCAT reactivity with SM-enriched HDL particles.
Highlights
Reduction of plasma LCAT activity has been observed in several conditions in which the size of HDL particles is increased; the mechanism of this reduction remains elusive
A similar observation has been made in other publications, in which the appearance of large HDL particles in plasma is described as accompanied by a decrease in the Esterified cholesterol (EC)/total cholesterol (TC) ratio in plasma or a decrease in LCAT activity, suggesting that this could be a general response to the accumulation of large HDL in plasma [17, 20, 40, 41]
Despite a 70% decrease in plasma LCAT activity, plasma LCAT mass, hepatic mRNA for LCAT, and plasma catabolism of LCAT are similar between hA-I human apolipoprotein A-I transgenic (Tg) and human apolipoprotein A-I transgenic (hA-I Tg) Scavenger receptor class B type I (SR-BI) 2/2 mice
Summary
Reduction of plasma LCAT activity has been observed in several conditions in which the size of HDL particles is increased; 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 2/2) mice. We conclude that the decreased EC/TC ratio in the plasma of hA-I Tg SR-BI 2/2 mice is attributed to a reduction in LCAT reactivity with SM-enriched HDL particles.—Lee, J-Y., R. SR-BI overexpression resulted in a decrease in plasma HDL cholesterol and an increase in biliary cholesterol concentration [8,9,10]. SR-BI knockout (SR-BI 2/2) mice showed an increase in plasma cholesterol concentration and a decrease in gallbladder cholesterol [13, 14]. This article is available online at http://www.jlr.org
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