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

AbstractMany 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 (zds1 Δerg3 Δpdr1 Δpdr3 Δ). Among1–3,1 showed restored growth activity at a dose of 80  µg/disc in the mutant yeast strain. This phenotype suggests that1 suppresses Ca2+-signaling of the mutant yeast through inhibition of glycogen synthase kinase-3 β (GSK-3β) or calcineurin pathways or both. From this result, the inhibitory activity of1–3 against GSK-3 β was further determined.1–3 showed potent inhibitory activity against GSK-3 β 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 of1–3. Acid1 inhibited glucose production at 25  µM in H4IIE cells. Our results would open up new possibilities for an anti-diabetic effect of1 and might provide important insights into understanding the biological properties of naturally occurring NMI FA.
Source: Lipids - Category: Lipidology Source Type: research