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Research ArticleCELLULAR AND MOLECULAR

Distinct Effects of Ketone Bodies on Down-Regulation of Cell Surface Insulin Receptor and Insulin Receptor Substrate-1 Phosphorylation in Adrenal Chromaffin Cells

Hiroki Yokoo, Tomokazu Saitoh, Seiji Shiraishi, Toshihiko Yanagita, Takashi Sugano, Shin-Ichi Minami, Hideyuki Kobayashi and Akihiko Wada
Journal of Pharmacology and Experimental Therapeutics March 2003, 304 (3) 994-1002; DOI: https://doi.org/10.1124/jpet.102.044115
Hiroki Yokoo
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Tomokazu Saitoh
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Seiji Shiraishi
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Toshihiko Yanagita
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Takashi Sugano
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Shin-Ichi Minami
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Hideyuki Kobayashi
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Akihiko Wada
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Abstract

Treatment (≧24 h) of cultured bovine adrenal chromaffin cells with ketoacidosis-related concentrations (≧3 mM) of acetoacetate (but not β-hydroxybutyrate, acetone, and acidic medium) caused a time- and concentration-dependent reduction of cell surface125I-insulin binding by ∼38%, with no change in theKd value. The reduction of125I-insulin binding returned to control nontreated level at 24 h after the washout of acetoacetate-treated cells. Acetoacetate did not increase the internalization rate of cell surface insulin receptor (IR), as measured in the presence of brefeldin A, an inhibitor of cell surface vesicular exit from thetrans-Golgi network. Acetoacetate (10 mM for 24 h) lowered cellular levels of the immunoreactive IR precursor molecule (∼190 kDa) and IR by 22 and 28%, respectively. Acetoacetate decreased IR mRNA levels by ∼23% as early as 6 h, producing their maximum plateau reduction at 12 and 24 h. The half-life of IR mRNA was shortened by acetoacetate from 13.6 to 9.5 h. Immunoprecipitation followed by immunoblot analysis revealed that insulin-induced (100 nM for 10 min) tyrosine-phosphorylation of insulin receptor substrate-1 (IRS-1) was attenuated by 56% in acetoacetate-treated cells, with no change in IRS-1 level. These results suggest that chronic treatment with acetoacetate selectively down-regulated the density of cell surface functional IR via lowering IR mRNA levels and IR synthesis, thereby retarding insulin-induced activation of IRS-1.

Footnotes

  • This study was supported in part by a grant-in-aid for the 21st Century COE (Centers of Excellence) Program (Life Science) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

  • DOI: 10.1124/jpet.102.044115

  • Abbreviations:
    FFA
    free fatty acids
    IR
    insulin receptors
    ER
    endoplasmic reticulum
    IRS-1
    insulin receptor substrate-1
    cPGI2
    6α-carba-prostaglandin I2
    GAPDH
    glyceraldehyde-3-phosphate-dehydrogenase
    DMSO
    dimethyl sulfoxide
    KRP
    Krebs-Ringer phosphate
    PAGE
    polyacrylamide gel electrophoresis
    SSC
    saline-sodium citrate
    PPAR
    peroxisome proliferator-activated receptors
    kb
    kilobase
    • Received September 5, 2002.
    • Accepted November 11, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 304 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 304, Issue 3
1 Mar 2003
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Research ArticleCELLULAR AND MOLECULAR

Distinct Effects of Ketone Bodies on Down-Regulation of Cell Surface Insulin Receptor and Insulin Receptor Substrate-1 Phosphorylation in Adrenal Chromaffin Cells

Hiroki Yokoo, Tomokazu Saitoh, Seiji Shiraishi, Toshihiko Yanagita, Takashi Sugano, Shin-Ichi Minami, Hideyuki Kobayashi and Akihiko Wada
Journal of Pharmacology and Experimental Therapeutics March 1, 2003, 304 (3) 994-1002; DOI: https://doi.org/10.1124/jpet.102.044115

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Research ArticleCELLULAR AND MOLECULAR

Distinct Effects of Ketone Bodies on Down-Regulation of Cell Surface Insulin Receptor and Insulin Receptor Substrate-1 Phosphorylation in Adrenal Chromaffin Cells

Hiroki Yokoo, Tomokazu Saitoh, Seiji Shiraishi, Toshihiko Yanagita, Takashi Sugano, Shin-Ichi Minami, Hideyuki Kobayashi and Akihiko Wada
Journal of Pharmacology and Experimental Therapeutics March 1, 2003, 304 (3) 994-1002; DOI: https://doi.org/10.1124/jpet.102.044115
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