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)

Biochem J. 2004 Mar 15;378(Pt 3):769-78. doi: 10.1042/BJ20031277.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyltransferases / biosynthesis
  • Acetyltransferases / genetics
  • Adenoviridae / genetics
  • Aminoimidazole Carboxamide / analogs & derivatives*
  • Aminoimidazole Carboxamide / pharmacology*
  • Animals
  • Apoptosis
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism*
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Fatty Acid Synthases / biosynthesis
  • Fatty Acid Synthases / genetics
  • Gene Expression / drug effects
  • Genetic Vectors
  • Glucose / antagonists & inhibitors*
  • Insulin / metabolism*
  • Islets of Langerhans / cytology
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism*
  • Lipids / biosynthesis*
  • Male
  • Rats
  • Rats, Wistar
  • Ribonucleotides / pharmacology*
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors*
  • Transduction, Genetic
  • Triglycerides / metabolism


  • CCAAT-Enhancer-Binding Proteins
  • DNA-Binding Proteins
  • Insulin
  • Lipids
  • Ribonucleotides
  • Srebf1 protein, rat
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors
  • Triglycerides
  • Aminoimidazole Carboxamide
  • Acetyltransferases
  • aminoglycoside N1-acetyltransferase
  • Fatty Acid Synthases
  • AICA ribonucleotide
  • Glucose