title: Over-expression of sterol-regulatory-element-binding protein-1c (SREBP1c) in rat pancreatic islets induces lipogenesis and decreases glucose-stimulated insulin release: modulation by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR).
abstract: Accumulation of intracellular lipid by pancreatic islet beta-cells has been proposed to inhibit normal glucose-regulated insulin secretion ('glucolipotoxicity'). In the present study, we determine whether over-expression in rat islets of the lipogenic transcription factor SREBP1c (sterol-regulatory-element-binding protein-1c) affects insulin release, and whether changes in islet lipid content may be reversed by activation of AMPK (AMP-activated protein kinase). Infection with an adenovirus encoding the constitutively active nuclear fragment of SREBP1c resulted in expression of the protein in approx. 20% of islet cell nuclei, with a preference for beta-cells at the islet periphery. Real-time PCR (TaqMan) analysis showed that SREBP1c up-regulated the expression of FAS (fatty acid synthase; 6-fold), acetyl-CoA carboxylase-1 (2-fold), as well as peroxisomal-proliferator-activated receptor-gamma (7-fold), uncoupling protein-2 (1.4-fold) and Bcl2 (B-cell lymphocytic-leukaemia proto-oncogene 2; 1.3-fold). By contrast, levels of pre-proinsulin, pancreatic duodenal homeobox-1, glucokinase and GLUT2 (glucose transporter isoform-2) mRNAs were unaltered. SREBP1c-transduced islets displayed a 3-fold increase in triacylglycerol content, decreased glucose oxidation and ATP levels, and a profound inhibition of glucose-, but not depolarisation-, induced insulin secretion. Culture of islets with the AMPK activator 5-amino-4-imidazolecarboxamide riboside decreased the expression of the endogenous SREBP1c and FAS genes, and reversed the effect of over-expressing active SREBP1c on FAS mRNA levels and cellular triacylglycerol content. We conclude that SREBP1c over-expression, even when confined to a subset of beta-cells, leads to defective insulin secretion from islets and may contribute to some forms of Type II diabetes.
authors.affiliation: Henry Wellcome Signalling Laboratories and Department of Biochemistry, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Diraison
authors.forename: Laura
authors.initials: L
authors.lastname: Parton
authors.forename: Pascal
authors.initials: P
authors.lastname: Ferré
authors.forename: Fabienne
authors.initials: F
authors.lastname: Foufelle
authors.forename: Celia P
authors.initials: CP
authors.lastname: Briscoe
authors.forename: Isabelle
authors.initials: I
authors.lastname: Leclerc
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
mesh_terms: D000123:Acetyltransferases / Q000096:biosynthesis / Q000235:genetics; D000256:Adenoviridae / Q000235:genetics; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D064429:Fatty Acid Synthases / Q000096:biosynthesis / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D005822:Genetic Vectors; D005947:Glucose / Q000037:antagonists & inhibitors*; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008055:Lipids / Q000096:biosynthesis*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012265:Ribonucleotides / Q000494:pharmacology*; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014161:Transduction, Genetic; D014280:Triglycerides / Q000378:metabolism
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D007328:Insulin; D008055:Lipids; D012265:Ribonucleotides; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014280:Triglycerides; D000620:Aminoimidazole Carboxamide; D000123:Acetyltransferases; C055210:aminoglycoside N1-acetyltransferase; D064429:Fatty Acid Synthases; C031143:AICA ribonucleotide; D005947:Glucose