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-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.
Lee
Ji-Young
JY
Department of Pathology/Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Badeau
Robert M
RM
Mulya
Anny
A
Boudyguina
Elena
E
Gebre
Abraham K
AK
Smith
Thomas L
TL
Parks
John S
JS
D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism*; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007863:Lecithin Cholesterol Acyltransferase Deficiency / Q000235:genetics / Q000378:metabolism*; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics
D016632:Apolipoprotein A-I; D018955:CD36 Antigens; D008055:Lipids; D012333:RNA, Messenger; D007862:Phosphatidylcholine-Sterol O-Acyltransferase