Arachidonic Acid Inhibits the Insulin Induction of Glucose-6-phosphate Dehydrogenase via p38 MAP Kinase

• Published in: The Journal of biological chemistry 2005-12, Vol.280 (49), p.40660-40667
• Main Authors: Talukdar, Indrani, Szeszel-Fedorowicz, Wioletta, Salati, Lisa M.
• Format: Article
• Language: English
• Subjects: Animals; Arachidonic Acid - pharmacology; Cells, Cultured; Enzyme Activation - drug effects; Enzyme Induction - drug effects; Fatty Acids, Unsaturated - pharmacology; Gene Expression - drug effects; Glucosephosphate Dehydrogenase - antagonists & inhibitors; Glucosephosphate Dehydrogenase - biosynthesis; Glucosephosphate Dehydrogenase - genetics; Hepatocytes - enzymology; Insulin - pharmacology; Insulin Receptor Substrate Proteins; Male; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Phosphoproteins - metabolism; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Sprague-Dawley; RNA, Messenger - analysis; Serine - metabolism; Signal Transduction - drug effects; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M505531200

Polyunsaturated fatty acids are potent inhibitors of lipogenic gene expression in liver. The lipogenic enzyme glucose-6-phosphate dehydrogenase (G6PD) is unique in this gene family, in that fatty acids inhibit at a post-transcriptional step. In this study, we have provided evidence for a signaling pathway for the arachidonic acid inhibition of G6PD mRNA abundance. Arachidonic acid decreases the insulin induction of G6PD expression; by itself, arachidonic acid does not inhibit basal G6PD mRNA accumulation. The insulin stimulation of G6PD involves the phosphoinositide 3-kinase (PI 3-kinase) pathway (Wagle, A., Jivraj, S., Garlock, G. L., and Stapleton, S. R. (1998) J. Biol. Chem. 273, 14968-14974). Incubation of hepatocytes with arachidonic acid blocks the activation of PI 3-kinase by insulin as observed by a decrease in Ser473 phosphorylation of Akt, the downstream effector of PI 3-kinase. The decrease in PI 3-kinase activity was associated with an increase in Ser307 phosphorylation of IRS-1. Western analysis demonstrated increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) in arachidonic acid-treated cells, whereas extracellular signal-regulated kinase and c-Jun NH2-terminal kinase activity was not changed. Incubating the hepatocytes with the p38 MAPK inhibitor, SB203580, blocked the arachidonic acid inhibition of G6PD mRNA accumulation. Furthermore, SB203580 decreased the arachidonic acid-mediated Ser307 phosphorylation of IRS-1 and rescued Akt activation that was otherwise decreased by arachidonic acid. Thus, arachidonic acid inhibits the insulin stimulation of G6PD mRNA accumulation by stimulating the p38 MAPK pathway, thereby inhibiting insulin signal transduction.