Transgenic mice overexpressing nuclear SREBP-1c in pancreatic beta-cells.
Influx of excess fatty acids and the resultant accumulation of intracellular triglycerides are linked to impaired insulin secretion and action in the pathogenesis of type 2 diabetes. Sterol regulatory element-binding protein (SREBP)-1c is a transcription factor that controls cellular synthesis of fatty acids and triglycerides. SREBP-1c is highly expressed in high-energy and insulin-resistant states. To investigate effects of this synthetic lipid regulator on insulin secretion, we generated transgenic mice overexpressing nuclear SREBP-1c under the insulin promoter. beta-Cell-specific expression of SREBP-1c caused reduction in islet mass and impaired glucose-stimulated insulin secretion and was associated with accumulation of triglycerides, suppression of pancreas duodenal homeobox-1, and upregulation of uncoupling protein 2 gene expression. The mice presented with impaired glucose tolerance that was exacerbated by a high-energy diet. Taken together with enhanced insulin secretion from SREBP-1-null islets, these data suggest that SREBP-1c and endogenous lipogenesis could be involved in beta-cell dysfunction and diabetes.
Takahashi
Akimitsu
A
Department of Internal Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
Motomura
Kaori
K
Kato
Toyonori
T
Yoshikawa
Tomohiro
T
Nakagawa
Yoshimi
Y
Yahagi
Naoya
N
Sone
Hirohito
H
Suzuki
Hiroaki
H
Toyoshima
Hideo
H
Yamada
Nobuhiro
N
Shimano
Hitoshi
H
D000818:Animals; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics* / Q000502:physiology; D002467:Cell Nucleus / Q000502:physiology*; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D004032:Diet; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D018149:Glucose Intolerance / Q000235:genetics*; D018257:Helix-Loop-Helix Motifs; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D006946:Hyperinsulinism / Q000517:prevention & control; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D007473:Ion Channels; D007515:Islets of Langerhans / Q000378:metabolism / Q000502:physiology*; D026901:Membrane Transport Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D051381:Rats; D051780:Sterol Regulatory Element Binding Protein 1; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology; D000071246:Uncoupling Protein 2
D022762:CCAAT-Enhancer-Binding Proteins; D017931:DNA Primers; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D007328:Insulin; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; C497387:SREBF1 protein, human; C497388:Srebf1 protein, mouse; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D015534:Trans-Activators; D014157:Transcription Factors; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; C084010:pancreatic and duodenal homeobox 1 protein