title: Role of uncoupling protein-2 up-regulation and triglyceride accumulation in impaired glucose-stimulated insulin secretion in a beta-cell lipotoxicity model overexpressing sterol regulatory element-binding protein-1c.
abstract: Triglyceride (TG) accumulation in pancreatic beta-cells is thought to be associated with impaired insulin secretory response to glucose (lipotoxicity). To better understand the mechanism of the impaired insulin secretory response to glucose in beta-cell lipotoxicity, we overexpressed a constitutively active form of the sterol regulatory element-binding protein- 1c (SREBP-1c), a master transcriptional factor of lipogenesis, in INS-1 cells with an adenoviral vector. This treatment was associated with strong activation of transcription of the genes involved in fatty acid biosynthesis, increased cellular TG content, severely blunted glucose-stimulated insulin secretion, and enhanced expression of the uncoupling protein-2 (UCP-2), which supposedly dissipates the mitochondrial electrochemical potential. To decrease the up-regulated UCP-2 expression, small interfering RNA for UCP-2 was used. Introduction of the small interfering RNA increased the ATP/ADP ratio and partially rescued the glucose-stimulated insulin secretion in the cells overexpressing SREBP-1c, but did not affect the cellular TG content. Next, the effect of the AMP-activated protein kinase (AMPK) agonist, 5-amino-4-imidazolecarboxamide riboside, was examined in the lipotoxicity model. Exposure of the cells with lipotoxicity to 5-amino-4-imidazolecarboxamide riboside increased free fatty acid oxidation, partially reversed the TG accumulation, phosphorylated AMPK and acetyl-coenzyme A carboxylase, and improved the impaired glucose-stimulated insulin secretion. These results suggest that UCP-2 down-regulation and AMPK activation could be candidate targets for releasing beta-cells from lipotoxicity.
authors.affiliation: Department of Metabolic Diseases, University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan.
authors.forename: Tokuyuki
authors.initials: T
authors.lastname: Yamashita
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Eto
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Okazaki
authors.forename: Shigeo
authors.initials: S
authors.lastname: Yamashita
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Yamauchi
authors.forename: Nobuo
authors.initials: N
authors.lastname: Sekine
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Noda
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000032:analysis; D000255:Adenosine Triphosphate / Q000032:analysis; D000256:Adenoviridae / Q000235:genetics; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007473:Ion Channels; D007515:Islets of Langerhans / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000502:physiology*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D012265:Ribonucleotides / Q000494:pharmacology; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014280:Triglycerides / Q000378:metabolism*; D000071246:Uncoupling Protein 2; D015854:Up-Regulation
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D007328:Insulin; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; D012265:Ribonucleotides; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014280:Triglycerides; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; D000620:Aminoimidazole Carboxamide; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D000103:Acetyl-CoA Carboxylase; C031143:AICA ribonucleotide; D005947:Glucose