Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes.
Hepatic glucokinase plays a key role in glucose metabolism as underlined by the anomalies associated with glucokinase mutations and the consequences of tissue-specific knock-out. In the liver, glucokinase transcription is absolutely dependent on the presence of insulin. The cis-elements and trans-acting factors that mediate the insulin effect are presently unknown; this is also the case for most insulin-responsive genes. We have shown previously that the hepatic expression of the transcription factor sterol regulatory element binding protein-1c (SREBP-1c) is activated by insulin. We show here in primary cultures of hepatocytes that the adenovirus-mediated transduction of a dominant negative form of SREBP-1c inhibits the insulin effect on endogenous glucokinase expression. Conversely, in the absence of insulin, the adenovirus-mediated transduction of a dominant positive form of SREBP-1c overcomes the insulin dependency of glucokinase expression. Hepatic fatty acid synthase and Spot-14 are insulin/glucose-dependent genes. For this latter class of genes, the dominant positive form of SREBP-1c obviates the necessity for the presence of insulin, whereas glucose potentiates the effect of SREBP-1c on their expression. In addition, the insulin dependency of lipid accumulation in cultured hepatocytes is overcome by the dominant positive form of SREBP-1c. We propose that SREBP-1c is a major mediator of insulin action on hepatic gene expression and a key regulator of hepatic glucose/lipid metabolism.
Foretz
M
M
U465 Institut National de la Santé et de la Recherche Médicale, Centre de Recherches Biomédicales des Cordeliers, Université Paris 6, Paris, France.
Guichard
C
C
Ferré
P
P
Foufelle
F
F
D000818:Animals; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins; D002478:Cells, Cultured; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D064429:Fatty Acid Synthases / Q000235:genetics; D005227:Fatty Acids / Q000096:biosynthesis*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D005941:Glucokinase / Q000235:genetics*; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000502:physiology*; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors
D022762:CCAAT-Enhancer-Binding Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D007328:Insulin; D009687:Nuclear Proteins; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D064429:Fatty Acid Synthases; D005941:Glucokinase; D005947:Glucose