title: (4Z,15Z)-Octadecadienoic Acid Inhibits Glycogen Synthase Kinase-3β and Glucose Production in H4IIE Cells.
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 IC50values 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.
authors.affiliation: Center for Liberal Arts and Sciences, Iwate Medical University, Yahaba, Iwate, 028-3694, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Yoshida
authors.affiliation: The United Graduate School of Agricultural Sciences, Iwate University, Morioka, Iwate, 020-8550, Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Uesugi
authors.affiliation: Graduate School of Agriculture, Iwate University, Morioka, Iwate, 020-8550, Japan.
authors.forename: Tetsuaki
authors.initials: T
authors.lastname: Kawamura
authors.affiliation: The United Graduate School of Agricultural Sciences, Iwate University, Morioka, Iwate, 020-8550, Japan.|Graduate School of Agriculture, Iwate University, Morioka, Iwate, 020-8550, Japan.
authors.forename: Ken-Ichi
authors.initials: KI
authors.lastname: Kimura
authors.affiliation: Graduate School of Innovative Life Science, University of Toyama, 3190 Gofuku, Toyama, 930-8555, Japan.
authors.forename: Dawei
authors.initials: D
authors.lastname: Hu
authors.affiliation: Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama, 930-8555, Japan.
authors.forename: Shuang
authors.initials: S
authors.lastname: Xia
authors.affiliation: Graduate School of Innovative Life Science, University of Toyama, 3190 Gofuku, Toyama, 930-8555, Japan.|Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama, 930-8555, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Toyooka
authors.affiliation: Department of Food Science and Human Nutrition, Faculty of Human Life Sciences, Fuji Women's University, Ishikari, 061-3204, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Ohnishi
authors.affiliation: Bioscience Laboratory, Miyako College, Iwate Prefectural University, Miyako, 027-0039, Japan. ajoe@iwate-pu.ac.jp.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kawashima
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development*
chemical_list: D005231:Fatty Acids, Unsaturated; C027369:octadecadienoic acid; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D019703:Calcineurin; D005947:Glucose; D002118:Calcium
keywords: (12Z, 23Z)-Hexacosadienoic acid; (4Z, 15Z)-Octadecadienoic acid; (9Z, 20Z)-Tricosadienoic acid; GSK-3β; H4IIE cells; Non-methylene-interrupted fatty acid