Palmitate impairs and eicosapentaenoate restores insulin secretion through regulation of SREBP-1c in pancreatic islets

Toyonori Kato; Hitoshi Shimano; Takashi Yamamoto; Mayumi Ishikawa; Shin Kumadaki; Takashi Matsuzaka; Yoshimi Nakagawa; Naoya Yahagi; Masanori Nakakuki; Alyssa H. Hasty; Yoshinori Takeuchi; Kazuto Kobayashi; Akimitsu Takahashi; Shigeru Yatoh; Hiroaki Suzuki; Hirohito Sone; Nobuhiro Yamada

doi:10.2337/db06-1806

Palmitate impairs and eicosapentaenoate restores insulin secretion through regulation of SREBP-1c in pancreatic islets

Toyonori Kato, Hitoshi Shimano^*, Takashi Yamamoto, Mayumi Ishikawa, Shin Kumadaki, Takashi Matsuzaka, Yoshimi Nakagawa, Naoya Yahagi, Masanori Nakakuki, Alyssa H. Hasty, Yoshinori Takeuchi, Kazuto Kobayashi, Akimitsu Takahashi, Shigeru Yatoh, Hiroaki Suzuki, Hirohito Sone, Nobuhiro Yamada

^*Corresponding author for this work

Complex Biosystem Research, Institute of Natural Medicine

Research output: Contribution to journal › Article › peer-review

85 Scopus citations

Abstract

OBJECTIVE-Chronic exposure to fatty acids causes (β-cell failure, often referred to as lipotoxicity. We investigated its mechanisms, focusing on contribution of SREBP-1c, a key transcription factor for lipogenesis. RESEARCH DESIGN AND 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 (β-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-lc, accompanied by reciprocal changes of SREBP-lc target genes such as insulin receptor substrate-2 (IRS-2) and granuphilin. These palmitate-EPA effects on insulin secretion were abolished in SREBP-l-null islets. Suppression of IRS-2/Akt pathway could be a part of the downstream mechanism for the SREBP-lc-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-lc 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-lc plays a dominant role in palmitate- mediated insulin secretion defect, and EPA prevents it through SREBP-lc inhibition, implicating a therapeutic potential for treating diabetes related to lipotoxicity.

Original language	English
Pages (from-to)	2382-2392
Number of pages	11
Journal	Diabetes
Volume	57
Issue number	9
DOIs	https://doi.org/10.2337/db06-1806
State	Published - 2008/09

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism

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10.2337/db06-1806

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Kato, T., Shimano, H., Yamamoto, T., Ishikawa, M., Kumadaki, S., Matsuzaka, T., Nakagawa, Y., Yahagi, N., Nakakuki, M., Hasty, A. H., Takeuchi, Y., Kobayashi, K., Takahashi, A., Yatoh, S., Suzuki, H., Sone, H., & Yamada, N. (2008). Palmitate impairs and eicosapentaenoate restores insulin secretion through regulation of SREBP-1c in pancreatic islets. Diabetes, 57(9), 2382-2392. https://doi.org/10.2337/db06-1806

@article{94318014f87b4213a0281427def1a902,

title = "Palmitate impairs and eicosapentaenoate restores insulin secretion through regulation of SREBP-1c in pancreatic islets",

abstract = "OBJECTIVE-Chronic exposure to fatty acids causes (β-cell failure, often referred to as lipotoxicity. We investigated its mechanisms, focusing on contribution of SREBP-1c, a key transcription factor for lipogenesis. RESEARCH DESIGN AND 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 (β-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-lc, accompanied by reciprocal changes of SREBP-lc target genes such as insulin receptor substrate-2 (IRS-2) and granuphilin. These palmitate-EPA effects on insulin secretion were abolished in SREBP-l-null islets. Suppression of IRS-2/Akt pathway could be a part of the downstream mechanism for the SREBP-lc-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-lc 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-lc plays a dominant role in palmitate- mediated insulin secretion defect, and EPA prevents it through SREBP-lc inhibition, implicating a therapeutic potential for treating diabetes related to lipotoxicity.",

author = "Toyonori Kato and Hitoshi Shimano and Takashi Yamamoto and Mayumi Ishikawa and Shin Kumadaki and Takashi Matsuzaka and Yoshimi Nakagawa and Naoya Yahagi and Masanori Nakakuki and Hasty, {Alyssa H.} and Yoshinori Takeuchi and Kazuto Kobayashi and Akimitsu Takahashi and Shigeru Yatoh and Hiroaki Suzuki and Hirohito Sone and Nobuhiro Yamada",

year = "2008",

month = sep,

doi = "10.2337/db06-1806",

language = "英語",

volume = "57",

pages = "2382--2392",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association Inc.",

number = "9",

}

Kato, T, Shimano, H, Yamamoto, T, Ishikawa, M, Kumadaki, S, Matsuzaka, T, Nakagawa, Y, Yahagi, N, Nakakuki, M, Hasty, AH, Takeuchi, Y, Kobayashi, K, Takahashi, A, Yatoh, S, Suzuki, H, Sone, H & Yamada, N 2008, 'Palmitate impairs and eicosapentaenoate restores insulin secretion through regulation of SREBP-1c in pancreatic islets', Diabetes, vol. 57, no. 9, pp. 2382-2392. https://doi.org/10.2337/db06-1806

TY - JOUR

T1 - Palmitate impairs and eicosapentaenoate restores insulin secretion through regulation of SREBP-1c in pancreatic islets

AU - Kato, Toyonori

AU - Shimano, Hitoshi

AU - Yamamoto, Takashi

AU - Ishikawa, Mayumi

AU - Kumadaki, Shin

AU - Matsuzaka, Takashi

AU - Nakagawa, Yoshimi

AU - Yahagi, Naoya

AU - Nakakuki, Masanori

AU - Hasty, Alyssa H.

AU - Takeuchi, Yoshinori

AU - Kobayashi, Kazuto

AU - Takahashi, Akimitsu

AU - Yatoh, Shigeru

AU - Suzuki, Hiroaki

AU - Sone, Hirohito

AU - Yamada, Nobuhiro

PY - 2008/9

Y1 - 2008/9

N2 - OBJECTIVE-Chronic exposure to fatty acids causes (β-cell failure, often referred to as lipotoxicity. We investigated its mechanisms, focusing on contribution of SREBP-1c, a key transcription factor for lipogenesis. RESEARCH DESIGN AND 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 (β-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-lc, accompanied by reciprocal changes of SREBP-lc target genes such as insulin receptor substrate-2 (IRS-2) and granuphilin. These palmitate-EPA effects on insulin secretion were abolished in SREBP-l-null islets. Suppression of IRS-2/Akt pathway could be a part of the downstream mechanism for the SREBP-lc-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-lc 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-lc plays a dominant role in palmitate- mediated insulin secretion defect, and EPA prevents it through SREBP-lc inhibition, implicating a therapeutic potential for treating diabetes related to lipotoxicity.

AB - OBJECTIVE-Chronic exposure to fatty acids causes (β-cell failure, often referred to as lipotoxicity. We investigated its mechanisms, focusing on contribution of SREBP-1c, a key transcription factor for lipogenesis. RESEARCH DESIGN AND 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 (β-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-lc, accompanied by reciprocal changes of SREBP-lc target genes such as insulin receptor substrate-2 (IRS-2) and granuphilin. These palmitate-EPA effects on insulin secretion were abolished in SREBP-l-null islets. Suppression of IRS-2/Akt pathway could be a part of the downstream mechanism for the SREBP-lc-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-lc 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-lc plays a dominant role in palmitate- mediated insulin secretion defect, and EPA prevents it through SREBP-lc inhibition, implicating a therapeutic potential for treating diabetes related to lipotoxicity.

UR - http://www.scopus.com/inward/record.url?scp=52749087214&partnerID=8YFLogxK

U2 - 10.2337/db06-1806

DO - 10.2337/db06-1806

M3 - 学術論文

C2 - 18458149

AN - SCOPUS:52749087214

SN - 0012-1797

VL - 57

SP - 2382

EP - 2392

JO - Diabetes

JF - Diabetes

IS - 9

ER -

Palmitate impairs and eicosapentaenoate restores insulin secretion through regulation of SREBP-1c in pancreatic islets

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