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J Biol Chem ; 276(26): 23304-11, 2001 Jun 29.
Article in English | MEDLINE | ID: mdl-11323427

ABSTRACT

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 ( approximately 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 approximately 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 approximately 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.


Subject(s)
Apolipoproteins B/biosynthesis , Cholesterol 7-alpha-Hydroxylase/physiology , Liver/enzymology , Animals , Apolipoprotein B-100 , Apolipoproteins B/blood , Apolipoproteins B/metabolism , Bile Acids and Salts/metabolism , CCAAT-Enhancer-Binding Proteins/biosynthesis , CCAAT-Enhancer-Binding Proteins/genetics , Carrier Proteins/metabolism , Cholesterol/metabolism , Cholesterol 7-alpha-Hydroxylase/genetics , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/genetics , Hyperlipidemias/blood , Lipid Metabolism , Lipids/blood , Liver/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , RNA, Messenger/biosynthesis , Receptors, LDL/biosynthesis , Receptors, LDL/genetics , Sterol Regulatory Element Binding Protein 1 , Sterol Regulatory Element Binding Protein 2 , Taurochenodeoxycholic Acid/metabolism , Transcription Factors/biosynthesis , Transcription Factors/genetics , Triglycerides/blood
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