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(Received for publication, January 2, 1997)
From the Molecular Disease Branch and the § Laboratory
of Animal Medicine and Surgery, NHLBI, National Institutes of
Health, Bethesda, Maryland 20892-1666
We have established a mouse model for human LCAT
deficiency by performing targeted disruption of the LCAT gene in mouse
embryonic stem cells. Homozygous LCAT-deficient mice were healthy at
birth and fertile. Compared with age-matched wild-type littermates, the
LCAT activity in heterozygous and homozygous knockout mice was reduced
by 30 and 99%, respectively. LCAT deficiency resulted in significant
reductions in the plasma concentrations of total cholesterol, HDL
cholesterol, and apoA-I in both LCAT
Volume 272, Number 11,
Issue of March 14, 1997
pp. 7506-7510
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
GENERATION OF A NEW ANIMAL MODEL FOR HUMAN LCAT DEFICIENCY
/ mice (25, 7, and 12%;
p < 0.001 of normal) and LCAT +/ mice (65 and 59%;
p < 0.001 and 81%; not significant,
p = 0.17 of normal). In addition, plasma triglycerides
were significantly higher (212% of normal; p < 0.01)
in male homozygous knockout mice compared with wild-type animals but
remained normal in female knockout LCAT mice. Analyses of plasma
lipoproteins by fast protein liquid chromatography and two-dimensional
gel electrophoresis demonstrated the presence of heterogenous
pre
-migrating HDL, as well as triglyceride-enriched very low density
lipoprotein. After 3 weeks on a high-fat high-cholesterol diet, LCAT
/ mice had significantly lower plasma concentrations of total
cholesterol, reflecting reduced levels of both proatherogenic apoB-containing lipoproteins as well as HDL, compared with controls. Thus, we demonstrate for the first time that the absence of LCAT attenuates the rise of apoB-containing lipoproteins in response to
dietary cholesterol. No evidence of corneal opacities or renal insufficiency was detected in 4-month-old homozygous knockout mice. The
availability of a homozygous animal model for human LCAT deficiency
states will permit further evaluation of the role that LCAT plays in
atherosclerosis as well as the feasibility of performing gene transfer
in human LCAT deficiency states.
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