RGD Reference Report - Down-regulation of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by insulin: the role of the forkhead transcription factor FKHRL1. - Rat Genome Database

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Down-regulation of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by insulin: the role of the forkhead transcription factor FKHRL1.

Authors: Nadal, A  Marrero, PF  Haro, D 
Citation: Nadal A, etal., Biochem J. 2002 Aug 15;366(Pt 1):289-97.
RGD ID: 1599891
Pubmed: PMID:12027802   (View Abstract at PubMed)
PMCID: PMC1222772   (View Article at PubMed Central)
DOI: DOI:10.1042/BJ20020598   (Journal Full-text)

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 211 bp 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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cellular response to insulin stimulus  IEP 1599891 RGD 
response to peptide hormone  IEP 1599891 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Hmgcs2  (3-hydroxy-3-methylglutaryl-CoA synthase 2)


Additional Information