The transcription factor SREBP-1c is instrumental in the development of beta-cell dysfunction.
Accumulation of lipids in non-adipose tissues is often associated with Type 2 diabetes and its complications. Elevated expression of the lipogenic transcription factor, sterol regulatory element binding protein-1c (SREBP-1c), has been demonstrated in islets and liver of diabetic animals. To elucidate the molecular mechanisms underlying SREBP-1c-induced beta-cell dysfunction, we employed the Tet-On inducible system to achieve tightly controlled and conditional expression of the nuclear active form of SREBP-1c (naSREBP-1c) in INS-1 cells. Controlled expression of naSREBP-1c induced massive accumulation of lipid droplets and blunted nutrient-stimulated insulin secretion in INS-1 cells. K(+)-evoked insulin exocytosis was unaltered. Quantification of the gene expression profile in this INS-1 stable clone revealed that naSREBP-1c induced beta-cell dysfunction by targeting multiple genes dedicated to carbohydrate metabolism, lipid biosynthesis, cell growth, and apoptosis. naSREBP-1c elicits cell growth-arrest and eventually apoptosis. We also found that the SREBP-1c processing in beta-cells was irresponsive to acute stimulation of glucose and insulin, which was distinct from that in lipogenic tissues. However, 2-day exposure to these agents promoted SREBP-1c processing. Therefore, the SREBP-1c maturation could be implicated in the pathogenesis of beta-cell glucolipotoxicity.
Wang
Haiyan
H
Department of Internal Medicine, University Medical Centre, Geneva-4 CH-1211, Switzerland. Haiyan.Wang@medicine.unige.ch
Maechler
Pierre
P
Antinozzi
Peter A
PA
Herrero
Laura
L
Hagenfeldt-Johansson
Kerstin A
KA
Bjorklund
Anneli
A
Wollheim
Claes B
CB
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis* / Q000502:physiology; D002999:Clone Cells; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D007515:Islets of Langerhans / Q000378:metabolism / Q000503:physiopathology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000502:physiology
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D005947:Glucose