Mammalian Genome

, Volume 12, Issue 4, pp 295–298

Identification of a mutation in ADD1/SREBP-1 in the spontaneously hypertensive rat

  • Michal  Pravenec
  • Petr  Jansa
  • Vlastimil  Kostka
  • Václav  Zídek
  • Vladimír  Křen
  • Jiří Forejt
  • Theodore W.  Kurtz
Article

DOI: 10.1007/s003350010273

Cite this article as:
Pravenec, M., Jansa, P., Kostka, V. et al. Incorporating Mouse Genome (2001) 12: 295. doi:10.1007/s003350010273

Abstract.

It has recently been proposed that primary mutations in genes involved in fatty acid and lipid metabolism may contribute to the pathogenesis of insulin resistance and dyslipidemia often observed in spontaneous forms of hypertension. In the current study in the spontaneously hypertensive rat (SHR), we mapped and sequenced the gene encoding a key transcription factor known as ADD1 (adipocyte determination and differentiation factor 1) or SREBP-1c (sterol regulatory element binding protein-1c) that has recently been identified as a master regulator of genes involved in the hepatic control of lipid and carbohydrate metabolism. We found that (1) the gene for ADD1/SREBP-1c maps to a region of rat Chromosome 10 previously reported to contain a quantitative trait locus involved in the regulation of hepatic cholesterol levels and (2) the SHR harbors a valine-to-methionine substitution in the COOH terminal portion of the ADD1/SREBP-1 protein that is not present in 44 other strains of laboratory rats. These findings, together with previous studies showing that transgenic expression of SREBP-1 isoforms has major effects on hepatic fatty acid and cholesterol biosynthesis, suggest that naturally occurring variation in the gene encoding the SREBP-1 isoforms might contribute to inherited variation in lipid metabolism in the SHR versus other strains of rats. These results should serve to motivate future transfection studies of the effect of the SHR mutant on SREBP-1 expression and activation in vitro, as well as the development of congenic and transgenic strains of SHR to investigate the effects of different variants of SREBP-1 on carbohydrate and lipid metabolism in vivo.

Copyright information

© Springer-Verlag New York Inc. 2001

Authors and Affiliations

  • Michal  Pravenec
    • 1
  • Petr  Jansa
    • 3
  • Vlastimil  Kostka
    • 1
  • Václav  Zídek
    • 1
  • Vladimír  Křen
    • 1
  • Jiří Forejt
    • 3
  • Theodore W.  Kurtz
    • 4
  1. 1.Institute of Physiology, Czech Academy of Sciences, Videnska 1083, 14220 Prague 4, Czech RepublicCS
  2. 2.Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, 12800 Prague, Czech RepublicCS
  3. 3.Institute of Molecular Genetics, Czech Academy of Sciences, 14220 Prague, Czech RepublicCS
  4. 4.Department of Laboratory Medicine, University of California, San Francisco, California 94143-0134, USAUS