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Research Article Free access | 10.1172/JCI2961

Activation of cholesterol synthesis in preference to fatty acid synthesis in liver and adipose tissue of transgenic mice overproducing sterol regulatory element-binding protein-2.

J D Horton, I Shimomura, M S Brown, R E Hammer, J L Goldstein, and H Shimano

Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.

Find articles by Horton, J. in: JCI | PubMed | Google Scholar

Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.

Find articles by Shimomura, I. in: JCI | PubMed | Google Scholar

Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.

Find articles by Brown, M. in: JCI | PubMed | Google Scholar

Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.

Find articles by Hammer, R. in: JCI | PubMed | Google Scholar

Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.

Find articles by Goldstein, J. in: JCI | PubMed | Google Scholar

Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.

Find articles by Shimano, H. in: JCI | PubMed | Google Scholar

Published June 1, 1998 - More info

Published in Volume 101, Issue 11 on June 1, 1998
J Clin Invest. 1998;101(11):2331–2339. https://doi.org/10.1172/JCI2961.
© 1998 The American Society for Clinical Investigation
Published June 1, 1998 - Version history
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Abstract

We produced transgenic mice that express a dominant-positive truncated form of sterol regulatory element-binding protein-2 (SREBP-2) in liver and adipose tissue. The encoded protein lacks the membrane-binding and COOH-terminal regulatory domains, and it is therefore not susceptible to negative regulation by cholesterol. Livers from the transgenic mice showed increases in mRNAs encoding multiple enzymes of cholesterol biosynthesis, the LDL receptor, and fatty acid biosynthesis. The elevations in mRNA for 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) synthase and HMG CoA reductase were especially marked (13-fold and 75-fold, respectively). As a result, the transgenic livers showed a 28-fold increase in the rate of cholesterol synthesis and a lesser fourfold increase in fatty acid synthesis, as measured by intraperitoneal injection of [3H]water. These results contrast with previously reported effects of dominant-positive SREBP-1a, which activated fatty acid synthesis more than cholesterol synthesis. In adipose tissue of the SREBP-2 transgenics, the mRNAs for cholesterol biosynthetic enzymes were elevated, but the mRNAs for fatty acid biosynthetic enzymes were not. We conclude that SREBP-2 is a relatively selective activator of cholesterol synthesis, as opposed to fatty acid synthesis, in liver and adipose tissue of mice.

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