Palmitate impairs and eicosapentaenoate restores insulin secretion through regulation of SREBP-1c in pancreatic islets.
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.
Kato
Toyonori
T
Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
Shimano
Hitoshi
H
Yamamoto
Takashi
T
Ishikawa
Mayumi
M
Kumadaki
Shin
S
Matsuzaka
Takashi
T
Nakagawa
Yoshimi
Y
Yahagi
Naoya
N
Nakakuki
Masanori
M
Hasty
Alyssa H
AH
Takeuchi
Yoshinori
Y
Kobayashi
Kazuto
K
Takahashi
Akimitsu
A
Yatoh
Shigeru
S
Suzuki
Hiroaki
H
Sone
Hirohito
H
Yamada
Nobuhiro
N
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
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