Normal physiological responses to carbohydrate shortages cause the liver to increase the production of ketone bodies from the acetyl-CoA generated from fatty acid oxidation. This allows the use of ketone bodies for energy, thereby preserving the limited glucose for use by the brain. This adaptative response is switched off by insulin rapidly inhibiting the expression of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (HMGCS2) gene, which is a key control site of ketogenesis. We decided to investigate the molecular mechanism of this inhibition. In the present study, we show that FKHRL1, a member of the forkhead in rhabdosarcoma (FKHR) subclass of the Fox family of transcription factors, stimulates transcription from transfected 3-hydroxy-3-methylglutaryl-CoA synthase promoter-luciferase reporter constructs, and that this stimulation is repressed by insulin. An FKHRL1-responsive sequence AAAAATA, located 211bp upstream of the HMGCS2 gene transcription start site, was identified by deletion analysis. It binds FKHRL1 in vivo and in vitro and confers FKHRL1 responsiveness on homologous and heterologous promoters. If it is mutated, it partially blocks the effect of insulin in HepG2 cells, both in the absence and presence of overexpressed FKHRL1. These results suggest that FKHRL1 contributes to the regulation of HMGCS2 gene expression by insulin.
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August 2002
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Research Article|
August 15 2002
Down-regulation of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by insulin: the role of the forkhead transcription factor FKHRL1
Alícia NADAL;
Alícia NADAL
Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona, Avda. Diagonal, 643, E-08028 Barcelona, Spain
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Pedro F. MARRERO;
Pedro F. MARRERO
Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona, Avda. Diagonal, 643, E-08028 Barcelona, Spain
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Diego HARO
Diego HARO
1
Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona, Avda. Diagonal, 643, E-08028 Barcelona, Spain
1To whom correspondence should be addressed (e-mail dharo@farmacia.far.ub.es).
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Publisher: Portland Press Ltd
Received:
April 16 2002
Revision Received:
May 23 2002
Accepted:
May 23 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2002
2002
Biochem J (2002) 366 (1): 289–297.
Article history
Received:
April 16 2002
Revision Received:
May 23 2002
Accepted:
May 23 2002
Citation
Alícia NADAL, Pedro F. MARRERO, Diego HARO; Down-regulation of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by insulin: the role of the forkhead transcription factor FKHRL1. Biochem J 15 August 2002; 366 (1): 289–297. doi: https://doi.org/10.1042/bj20020598
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