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Research Article Free access | 10.1172/JCI119248

Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells.

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

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

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

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

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

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

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

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

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

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

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

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

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

Published March 1, 1997 - More info

Published in Volume 99, Issue 5 on March 1, 1997
J Clin Invest. 1997;99(5):846–854. https://doi.org/10.1172/JCI119248.
© 1997 The American Society for Clinical Investigation
Published March 1, 1997 - Version history
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Abstract

We have produced transgenic mice whose livers express a dominant positive NH2-terminal fragment of sterol regulatory element binding protein-1c (SREBP-1c). Unlike full-length SREBP-1c, the NH2-terminal fragment enters the nucleus without a requirement for proteolytic release from cell membranes, and hence it is immune to downregulation by sterols. We compared SREBP-1c transgenic mice with a line of transgenic mice that produces an equal amount of the NH2-terminal fragment of SREBP-1a. SREBP-1a and -1c are alternate transcripts from a single gene that differ in the first exon, which encodes part of an acidic activation domain. The 1a protein contains a long activation domain with 12 negatively charged amino acids, whereas the 1c protein contains a short activation domain with only 6 such amino acids. As previously reported, livers of the SREBP-1a transgenic mice were massively enlarged, owing to accumulation of triglycerides and cholesterol. SREBP-1c transgenic livers were only slightly enlarged with only a moderate increase in triglycerides, but not cholesterol. The mRNAs for the LDL receptor and several cholesterol biosynthetic enzymes were elevated in SREBP-la transgenic mice, but not in 1c transgenic mice. The mRNAs for fatty acid synthase and acetyl CoA carboxylase were elevated 9- and 16-fold in la animals, but only 2- and 4-fold in 1c animals. Experiments with transfected cells confirmed that SREBP-1c is a much weaker activator of transcription than SREBP-1a when both are expressed at levels approximating those found in nontransfected cells. SREBP-1c became a strong activator only when expressed at supraphysiologic levels. We conclude that SREBP-1a is the most active form of SREBP-1 and that SREBP-1c may be produced when cells require a lower rate of transcription of genes regulating cholesterol and fatty acid metabolism.

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