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(4Z,15Z)-Octadecadienoic Acid Inhibits Glycogen Synthase Kinase-3β and Glucose Production in H4IIE Cells

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Lipids

Abstract

Many uncommon non-methylene-interrupted fatty acids (NMI FA) are present in limpet gonads, but their biological properties remain unknown. To investigate new biological effects of naturally occurring NMI FA in eukaryotic cells, the biological activities of structurally analogous (4Z,15Z)-octadecadienoic acid (1), (9Z,20Z)-tricosadienoic acid (2), and (12Z,23Z)-hexacosadienoic acid (3) were examined by using a yeast-based drug-screening system using the Ca2+-sensitive mutant strain, Saccharomyces cerevisiae (zds1Δ erg3Δ pdr1Δ pdr3Δ). Among 1–3, 1 showed restored growth activity at a dose of 80 µg/disc in the mutant yeast strain. This phenotype suggests that 1 suppresses Ca2+-signaling of the mutant yeast through inhibition of glycogen synthase kinase-3β (GSK-3β) or calcineurin pathways or both. From this result, the inhibitory activity of 1–3 against GSK-3β was further determined. 1–3 showed potent inhibitory activity against GSK-3β with IC50 values ranging from 8.7 to 21.9 µM. Inhibition of GSK-3β reduces gene expression of the gluconeogenic key enzymes in liver, so we analyzed glucose production in rat hepatoma H4IIE cells to assess GSK-3β inhibitory activity of 1–3. Acid 1 inhibited glucose production at 25 µM in H4IIE cells. Our results would open up new possibilities for an anti-diabetic effect of 1 and might provide important insights into understanding the biological properties of naturally occurring NMI FA.

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Abbreviations

Ab:

Amyloid-β

Bt2cAMP:

N6,O2′-Dibutyryl adenosine 3′,5′-cyclic monophosphate

Dex:

Dexamethasone

DMEM:

Dulbecco’s modified Eagle’s medium

EI:

Electron ionization

FA:

Fatty acid(s)

FBS:

Fetal bovine serum

GSK-3β:

Glycogen synthase kinase-3β

HRMS:

High resolution mass spectrometry

IR:

Infrared spectroscopy

LNA:

Linoleic acid

MAPK:

Mitogen-activated protein kinase

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NMI:

Non-methylene-interrupted

NMR:

Nuclear magnetic resonance spectroscopy

MS:

Mass spectrum

PBS:

Phosphate buffered saline

PGSP-2:

Phospho-glycogen synthase peptide-2

PKC:

Protein kinase C

SD:

Standard deviation

TDZD-8:

4-Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione

YPD:

Yeast–peptone–dextrose

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Acknowledgements

This work was supported by a grant from the Keiryo-kai Research Foundation (Grant No.127).

Author information

Authors and Affiliations

  1. Center for Liberal Arts and Sciences, Iwate Medical University, Yahaba, Iwate, 028-3694, Japan

    Jun Yoshida

  2. The United Graduate School of Agricultural Sciences, Iwate University, Morioka, Iwate, 020-8550, Japan

    Shota Uesugi & Ken-ichi Kimura

  3. Graduate School of Agriculture, Iwate University, Morioka, Iwate, 020-8550, Japan

    Tetsuaki Kawamura & Ken-ichi Kimura

  4. Graduate School of Innovative Life Science, University of Toyama, 3190 Gofuku, Toyama, 930-8555, Japan

    Dawei Hu & Naoki Toyooka

  5. Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama, 930-8555, Japan

    Shuang Xia & Naoki Toyooka

  6. Department of Food Science and Human Nutrition, Faculty of Human Life Sciences, Fuji Women’s University, Ishikari, 061-3204, Japan

    Masao Ohnishi

  7. Bioscience Laboratory, Miyako College, Iwate Prefectural University, Miyako, 027-0039, Japan

    Hideki Kawashima

Authors
  1. Jun Yoshida
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  2. Shota Uesugi
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  3. Tetsuaki Kawamura
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  4. Ken-ichi Kimura
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  5. Dawei Hu
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  7. Naoki Toyooka
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  8. Masao Ohnishi
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  9. Hideki Kawashima
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Correspondence to Hideki Kawashima.

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Yoshida, J., Uesugi, S., Kawamura, T. et al. (4Z,15Z)-Octadecadienoic Acid Inhibits Glycogen Synthase Kinase-3β and Glucose Production in H4IIE Cells. Lipids 52, 295–301 (2017). https://doi.org/10.1007/s11745-017-4236-3

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  • DOI: https://doi.org/10.1007/s11745-017-4236-3

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