title: Stimulation of acetyl-CoA carboxylase gene expression by glucose requires insulin release and sterol regulatory element binding protein 1c in pancreatic MIN6 beta-cells.
abstract: Acetyl-CoA carboxylase I (ACCI) is a key lipogenic enzyme whose induction in islet beta-cells may contribute to glucolipotoxicity. Here, we provide evidence that enhanced insulin release plays an important role in the activation of this gene by glucose. Glucose (30 vs. 3 mmol/l) increased ACCI mRNA levels approximately 4-fold and stimulated ACCI (pII) promoter activity >30-fold in MIN6 cells. The latter effect was completely suppressed by blockade of insulin release or of insulin receptor signaling. However, added insulin substantially, but not completely, mimicked the effects of glucose, suggesting that intracellular metabolites of glucose may also contribute to transcriptional stimulation. Mutational analysis of the ACCI promoter, and antibody microinjection, revealed that the effect of glucose required sterol response element binding protein (SREBP)-1c. Moreover, adenoviral transduction with dominant-negative-acting SREBP1c blocked ACCI gene induction, whereas constitutively active SREBP1c increased ACCI mRNA levels. Finally, glucose also stimulated SREBP1c transcription, although this effect was independent of insulin release. These data suggest that glucose regulates ACCI gene expression in the beta-cell by complex mechanisms that may involve the covalent modification of SREBP1c. However, overexpression of SREBP1c also decreased glucose-stimulated insulin release, implicating SREBP1c induction in beta-cell lipotoxicity in some forms of type 2 diabetes.
authors.affiliation: Department of Biochemistry, University of Bristol, Bristol, UK.
authors.forename: Chrysovalantis
authors.initials: C
authors.lastname: Andreolas
authors.forename: Gabriela
authors.initials: G
authors.lastname: da Silva Xavier
authors.forename: Frederique
authors.initials: F
authors.lastname: Diraison
authors.forename: Chao
authors.initials: C
authors.lastname: Zhao
authors.forename: Aniko
authors.initials: A
authors.lastname: Varadi
authors.forename: Fernando
authors.initials: F
authors.lastname: Lopez-Casillas
authors.forename: Pascal
authors.initials: P
authors.lastname: Ferré
authors.forename: Fabienne
authors.initials: F
authors.lastname: Foufelle
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000235:genetics*; D000123:Acetyltransferases / Q000235:genetics*; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005822:Genetic Vectors; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014700:Verapamil / Q000494:pharmacology
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D007328:Insulin; D011994:Recombinant Proteins; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D011189:Potassium Chloride; D014700:Verapamil; D000123:Acetyltransferases; C055210:aminoglycoside N1-acetyltransferase; D000103:Acetyl-CoA Carboxylase; D005947:Glucose