Glucose-induced lipogenesis in pancreatic beta-cells is dependent on SREBP-1.
High concentrations of glucose induce de novo fatty acid synthesis in pancreatic beta-cells and chronic exposure of elevated glucose and fatty acids synergize to induce accumulation of triglycerides, a phenomenon termed glucolipotoxicity. Here we investigate the role of sterol-regulatory element binding proteins in glucose-induced lipogenesis in the pancreatic beta-cell line INS-1E. We show that glucose induces SREBP-1c expression and SREBP-1 activity independent of insulin secretion and signaling. Using adenoviral expression of SREBP-1c and a SREBP-mutant we show that lipogenic gene expression, de novo fatty acid synthesis and lipid accumulation are induced primarily through sterol-regulatory elements (SREs) and not E-Boxes. Adenoviral expression of a dominant negative SREBP compromises glucose induction of some lipogenic genes and significantly reduces glucose-induction of de novo fatty acid synthesis. Thus, we demonstrate for the first time that SREBP activity is necessary for full glucose induction of de novo fatty acid synthesis in pancreatic beta-cells.
Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense.
Maria B
MB
Sandberg
Jakob
J
Fridriksson
Lise
L
Madsen
Vikas
V
Rishi
Charles
C
Vinson
Holm
H
Holmsen
Rolf K
RK
Berge
Susanne
S
Mandrup
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation; D024721:E-Box Elements / Q000502:physiology; D005227:Fatty Acids / Q000096:biosynthesis*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005786:Gene Expression Regulation; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation; D051381:Rats; D020218:Response Elements / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects
D005227:Fatty Acids; D005231:Fatty Acids, Unsaturated; D007328:Insulin; D005947:Glucose