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J. Biol. Chem., Vol. 276, Issue 26, 23304-23311, June 29, 2001
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From the The finding that expression of a
cholesterol 7
Increased Production of Apolipoprotein B-containing Lipoproteins
in the Absence of Hyperlipidemia in Transgenic Mice Expressing
Cholesterol 7
-Hydroxylase*
,,,,
, and**
Mammalian Cell and Molecular Biology
Laboratory, San Diego State University, San Diego, California
92182-4614, the § Department of Microbiology and Molecular
Genetics, UCLA, Los Angeles, California 90095, the
¶ Scripps Research Institute, La Jolla, California 92037, and the
Gladstone Institute for Cardiovascular Disease, University of
California, San Francisco, California 94141
-hydroxylase (CYP7A1) transgene in cultured rat
hepatoma cells caused a coordinate increase in lipogenesis and
secretion of apoB-containing lipoproteins led to the hypothesis that
hepatic production of apoB-containing lipoproteins may be linked to the
expression of CYP7A1 (Wang, S.-L., Du, E., Martin, T. D., and
Davis, R. A. (1997) J. Biol. Chem. 272, 19351-19358). To examine this hypothesis in vivo, a transgene encoding CYP7A1 driven by the constitutive liver-specific enhancer of the human apoE gene was expressed in C56BL/6 mice. The
expression of CYP7A1 mRNA (20-fold), protein (~10-fold), and enzyme activity (5-fold) was markedly increased in transgenic mice
compared with non-transgenic littermates. The bile acid pool of CYP7A1
transgenic mice was doubled mainly due to increased hydrophobic
dihydroxy bile acids. In CYP7A1 transgenic mice, livers contained
~3-fold more sterol response element-binding protein-2 mRNA. Hepatic expression of mRNAs encoding lipogenic enzymes
(i.e. fatty-acid synthase, acetyl-CoA carboxylase,
stearoyl-CoA desaturase, squalene synthase, farnesyl-pyrophosphate
synthase, 3-hydroxy-3-methylglutaryl-CoA reductase, and low
density lipoprotein receptor) as well as microsomal triglyceride
transfer protein were elevated ~3-5-fold in transgenic mice. CYP7A1
transgenic mice also displayed a >2-fold increase in hepatic
production and secretion of triglyceride-rich apoB-containing lipoproteins. Despite the increased hepatic secretion of
apoB-containing lipoproteins in CYP7A1 mice, plasma levels of
triglycerides and cholesterol were not significantly increased. These
data suggest that the 5-fold increased expression of the low density
lipoprotein receptor displayed by the livers of CYP7A1 transgenic mice
was sufficient to compensate for the 2-fold increase production of apoB-containing lipoproteins. These findings emphasize the important homeostatic role that CYP7A1 plays in balancing the anabolic
lipoprotein assembly/secretion pathway with the cholesterol catabolic
bile acid synthetic pathway.
*
This work was supported by National Institutes of Health
Grants HL57974 and HL51648.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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