title: Palmitate impairs and eicosapentaenoate restores insulin secretion through regulation of SREBP-1c in pancreatic islets.
abstract: OBJECTIVE
  Chronic exposure to fatty acids causes beta-cell failure, often referred to as lipotoxicity. We investigated its mechanisms, focusing on contribution of SREBP-1c, a key transcription factor for lipogenesis.
  
  
  METHODS
  We studied in vitro and in vivo effects of saturated and polyunsaturated acids on insulin secretion, insulin signaling, and expression of genes involved in beta-cell functions. Pancreatic islets isolated from C57BL/6 control and SREBP-1-null mice and adenoviral gene delivery or knockdown systems of related genes were used.
  
  
  RESULTS
  Incubation of C57BL/6 islets with palmitate caused inhibition of both glucose- and potassium-stimulated insulin secretion, but addition of eicosapentaenoate (EPA) restored both inhibitions. Concomitantly, palmitate activated and EPA abolished both mRNA and nuclear protein of SREBP-1c, accompanied by reciprocal changes of SREBP-1c target genes such as insulin receptor substrate-2 (IRS-2) and granuphilin. These palmitate-EPA effects on insulin secretion were abolished in SREBP-1-null islets. Suppression of IRS-2/Akt pathway could be a part of the downstream mechanism for the SREBP-1c-mediated insulin secretion defect because adenoviral constitutively active Akt compensated it. Uncoupling protein-2 (UCP-2) also plays a crucial role in the palmitate inhibition of insulin secretion, as confirmed by knockdown experiments, but SREBP-1c contribution to UCP-2 regulation was partial. The palmitate-EPA regulation of insulin secretion was similarly observed in islets from C57BL/6 mice pretreated with dietary manipulations. Furthermore, administration of EPA to diabetic KK-Ay mice ameliorated impairment of insulin secretion in their islets.
  
  
  CONCLUSIONS
  SREBP-1c plays a dominant role in palmitate-mediated insulin secretion defect, and EPA prevents it through SREBP-1c inhibition, implicating a therapeutic potential for treating diabetes related to lipotoxicity.
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, 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: Mayumi
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Shin
authors.initials: S
authors.lastname: Kumadaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsuzaka
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Naoya
authors.initials: N
authors.lastname: Yahagi
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakakuki
authors.forename: Alyssa H
authors.initials: AH
authors.lastname: Hasty
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Takeuchi
authors.forename: Kazuto
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Akimitsu
authors.initials: A
authors.lastname: Takahashi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yatoh
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Suzuki
authors.forename: Hirohito
authors.initials: H
authors.lastname: Sone
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Yamada
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015118:Eicosapentaenoic Acid / Q000378:metabolism / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D020868:Gene Silencing; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D000078790:Insulin Secretion; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D050155:Lipogenesis / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009924:Organ Culture Techniques; D010168:Palmitates / Q000633:toxicity*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D000071246:Uncoupling Protein 2
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007473:Ion Channels; C526298:Irs2 protein, mouse; D024101:Mitochondrial Proteins; D010168:Palmitates; D010750:Phosphoproteins; D012333:RNA, Messenger; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D015118:Eicosapentaenoic Acid; D051057:Proto-Oncogene Proteins c-akt