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Originally published In Press as doi:10.1074/jbc.M101853200 on April 25, 2001

J. Biol. Chem., Vol. 276, Issue 26, 23304-23311, June 29, 2001
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Increased Production of Apolipoprotein B-containing Lipoproteins in the Absence of Hyperlipidemia in Transgenic Mice Expressing Cholesterol 7alpha -Hydroxylase*

Jon H. MiyakeDagger , Xuan-Dao T. DoungDagger , William StraussDagger , Gina L. MooreDagger , Lawrence W. Castellani§, Linda K. Curtiss, John M. Taylor||, and Roger A. DavisDagger **

From the Dagger  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

The finding that expression of a cholesterol 7alpha -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.

** To whom correspondence should be addressed: Mammalian Cell and Molecular Biology Lab., Life Sciences Bldg. LS307, 5500 Campanile Dr., San Diego State University, San Diego, CA 92182-4614. Tel.: 619-594-7936; Fax: 619-594-7937; E-mail: rdavis@sunstroke.sdsu.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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