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Journal of Lipid Research, Vol 38, 1033-1047, Copyright © 1997 by Lipid Research, Inc.
AS Plump, N Azrolan, H Odaka, L Wu, X Jiang, A Tall, S Eisenberg and JL Breslow
The major high density lipoprotein (HDL) apolipoprotein, apoA-I, was
knocked out by gene targeting in ES cells to provide a model for the study
of HDL metabolism and its relationship to plasma and tissue cholesterol
metabolism. HDL and non-HDL cholesterol (HDL-C) were reduced in
apoA-I-deficient mice. Feeding a high fat-high cholesterol diet raised
HDL-C minimally in apoA-I knockout compared to the large increase seen in
control mice, suggesting an interaction between diet and apoA-I genotype.
In apoA-I-deficient mice, HDL was normal in size but altered in
composition. Compared to control mice there was more triglyceride and free
cholesterol and less cholesteryl ester (CE), suggesting that
apoA-I-deficient HDL is a poor substrate for hepatic lipase and
lecithin:cholesterol acyltransferase (LCAT). The metabolic basis of the low
HDL-C levels in the apoA-I knockout mice was decreased flux into the HDL CE
pool. The absolute delivery of HDL CE to both peripheral tissues and liver
was also decreased. As tissue cholesterol levels and synthesis were
unchanged, the decreased flux of cholesterol into the HDL CE pool was most
likely due to decreased efflux of cholesterol from the peripheral tissues
and decreased functional LCAT activity. The low HDL-C state in the
apoA-I-deficient mouse was associated with an absolute decrease in
unidirectional transport of cholesterol from peripheral tissues to the
liver but this did not lead to cholesterol accumulation in the periphery or
a cholesterol deficit in the liver; nor was there altered peripheral tissue
HMG-CoA reductase activity. The only sign of decreased cholesterol flux to
the liver was a 2.3-fold decrease in liver cholesterol 7 alpha-hydroxylase
mRNA, suggesting decreased bile acid synthesis. In the apoA-I knockout
mouse model it appears that low HDL levels create a new steady state in
which decreased cholesterol is delivered to both peripheral tissues and the
liver.
ARTICLES
ApoA-I knockout mice: characterization of HDL metabolism in homozygotes and identification of a post-RNA mechanism of apoA-I up-regulation in heterozygotes
Laboratory of Biochemical, Genetics, and Metabolism, Rockefeller University, New York, NY 10021, USA.
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