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

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.