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(4 Z ,15 Z )‐Octadecadienoic Acid Inhibits Glycogen Synthase Kinase‐3β and Glucose Production in H4IIE Cells
Author(s) -
Yoshida Jun,
Uesugi Shota,
Kawamura Tetsuaki,
Kimura Kenichi,
Hu Dawei,
Xia Shuang,
Toyooka Naoki,
Ohnishi Masao,
Kawashima Hideki
Publication year - 2017
Publication title -
lipids
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.601
H-Index - 120
eISSN - 1558-9307
pISSN - 0024-4201
DOI - 10.1007/s11745-017-4236-3
Subject(s) - glycogen synthase , yeast , biochemistry , saccharomyces cerevisiae , mutant , gsk 3 , biology , enzyme , kinase , chemistry , gene
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 (4 Z ,15 Z )‐octadecadienoic acid ( 1 ), (9 Z ,20 Z )‐tricosadienoic acid ( 2 ), and (12 Z ,23 Z )‐hexacosadienoic acid ( 3 ) were examined by using a yeast‐based drug‐screening system using the Ca 2+ ‐sensitive mutant strain, Saccharomyces cerevisiae ( zds 1Δ erg 3Δ pdr 1Δ pdr 3Δ). 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 Ca 2+ ‐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 IC 50 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.