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Increased production of apolipoprotein B-containing lipoproteins in the absence of hyperlipidemia in transgenic mice expressing cholesterol 7α-hydroxylase

Academic Article
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Overview

authors

  • Miyake, J. H.
  • Doung, X. D. T.
  • Strauss, W.
  • Moore, G. L.
  • Castellani, L. W.
  • Curtiss, Linda
  • Taylor, J. M.
  • Davis, R. A.

publication date

  • 2001

journal

  • Journal of Biological Chemistry  Journal

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 areas

  • Animals
  • Apolipoprotein B-100
  • Apolipoproteins B
  • Bile Acids and Salts
  • CCAAT-Enhancer-Binding Proteins
  • Carrier Proteins
  • Cholesterol
  • Cholesterol 7-alpha-Hydroxylase
  • DNA-Binding Proteins
  • Hyperlipidemias
  • Lipid Metabolism
  • Lipids
  • Liver
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • RNA, Messenger
  • Receptors, LDL
  • Sterol Regulatory Element Binding Protein 1
  • Sterol Regulatory Element Binding Protein 2
  • Taurochenodeoxycholic Acid
  • Transcription Factors
  • Triglycerides
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Identity

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M101853200

PubMed ID

  • 11323427
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Additional Document Info

start page

  • 23304

end page

  • 23311

volume

  • 276

issue

  • 26

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