Oleoylethanolamide, a natural ligand for PPAR-alpha, inhibits insulin receptor signalling in HTC rat hepatoma cells

Oleoylethanolamide (OEA) is a lipid mediator belonging to the fatty acid ethanolamides family. It is produced by intestine and adipose tissue. it inhibits food intake and body weight gain, and has hypolipemiant action in vivo, as well as a lipolytic effect in vitro. OEA is a PPAR-alpha agonist, and recently it has been found that OEA is an endogenous ligand of an orphan receptor. Previously, we have shown that OEA inhibits insulin-stimulated glucose uptake in isolated adipocytes, and produces glucose intolerance in rats. In the present work, we have studied another insulin target cell, the hepatocyte using a rat hepatoma cell line (HTC), and we have studied the cross-talk of OEA signalling with metabolic and mitotic signal transduction of insulin receptor. OEA dose-dependently activates JNK and p38 MAPK, and inhibits insulin receptor phosphorylation. OEA inhibits insulin receptor activation, blunting insulin signalling in the downstream PI3K pathway, decreasing phosphorylation of PKB and its target GSK-3. OEA also inhibits insulin-dependent MAPK pathway, as assessed by immunoblot of phosphorylated MEK and MAPK. These effects were reversed by blocking JNK or p38 MAPK using pharmacological inhibitors (SP 600125, and SB 203580). Since OEA is an endogenous PPAR-alpha agonist, we investigated whether a pharmacologic agonist (WY 14643) may mimic the OEA effect on insulin receptor signalling. Activation of PPAR-alpha by the pharmacological agonist WY14643 in HTC hepatoma cells is sufficient to inhibit insulin signalling and this effect is also dependent on p38 MAPK but not JNK kinase. In summary, OEA inhibits insulin metabolic and mitogenic signalling by activation of JNK and p38 MAPK via PPAR-alpha. (C) 2009 Elsevier B.V. All rights reserved.