title: Granuphilin is activated by SREBP-1c and involved in impaired insulin secretion in diabetic mice.
abstract: Granuphilin is a crucial component of the docking machinery of insulin-containing vesicles to the plasma membrane. Here, we show that the granuphilin promoter is a target of SREBP-1c, a transcription factor that controls fatty acid synthesis, and MafA, a beta cell differentiation factor. Potassium-stimulated insulin secretion (KSIS) was suppressed in islets with adenoviral-mediated overexpression of granuphilin and enhanced in islets with knockdown of granuphilin (in which granuphilin had been knocked down). SREBP-1c and granuphilin were activated in islets from beta cell-specific SREBP-1c transgenic mice, as well as in several diabetic mouse models and normal islets treated with palmitate, accompanied by a corresponding reduction in insulin secretion. Knockdown- or knockout-mediated ablation of granuphilin or SREBP-1c restored KSIS in these islets. Collectively, our data provide evidence that activation of the SREBP-1c/granuphilin pathway is a potential mechanism for impaired insulin secretion in diabetes, contributing to beta cell lipotoxicity.
authors.affiliation: Department of Internal Medicine, Endocrinology and Metabolism, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba Ibaraki 305-8575, Japan.
authors.forename: Toyonori
authors.initials: T
authors.lastname: Kato
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shimano
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Tomotaka
authors.initials: T
authors.lastname: Yokoo
authors.forename: Yuko
authors.initials: Y
authors.lastname: Endo
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsuzaka
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Shin
authors.initials: S
authors.lastname: Kumadaki
authors.forename: Naoya
authors.initials: N
authors.lastname: Yahagi
authors.forename: Akimitsu
authors.initials: A
authors.lastname: Takahashi
authors.forename: Hirohito
authors.initials: H
authors.lastname: Sone
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Suzuki
authors.forename: Hideo
authors.initials: H
authors.lastname: Toyoshima
authors.forename: Alyssa H
authors.initials: AH
authors.lastname: Hasty
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Gomi
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Izumi
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Yamada
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D051473:Maf Transcription Factors, Large / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010168:Palmitates / Q000494:pharmacology / Q000633:toxicity; D011188:Potassium / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism / Q000494:pharmacology*; D033921:Vesicular Transport Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*
chemical_list: D007328:Insulin; D051473:Maf Transcription Factors, Large; C485160:Mafa protein, mouse; D010168:Palmitates; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; C122015:Sytl4 protein, mouse; D033921:Vesicular Transport Proteins; D011188:Potassium