Lipid-induced p62dok up-regulation enhances hepatic gluconeogenesis

AIM:To investigate the potential role of p62^dok in the regulation of hepatic gluconeogenesis. METHODS:The expression of p62^dok, insulin signaling transduction, and hepatic gluconeogenesis were investigated in the liver tissues of mice treated with high-fat diet(HFD) and in cultured mouse hepatocytes treated with free fatty acid(FFA). The experiments of gene silencing and overexpression were conducted to observe the effects of p62^dok on insulin signal transduction and hepatic gluconeogenesis in cultured mouse hepatocytes. Western blotting was used to detect the protein levels and the phosphorylation statue. RESULTS:The increased p62^dok levels were found in the liver tissues from HFD-treated mice and FFA-treated hepatocytes. Meanwhile, phosphorylation of Akt and forkhead box O1 protein(FoxO1) was were decreased and the expression of glucose-6-phosphatase(G6Pase) and phosphoenolpyruvate carboxykinase(PEPCK) was increased. Silencing of p62^dok in cultured hepatocytes treated with FFA induced the increase in phosphorylation of Akt and FoxO1, and decrease in the protein levels of G6Pase and PEPCK. CONCLUSION:Up-regulation of p62^dok induced by HFD or FFA enhances hepatic gluconeogenesis via inhibiting insulin signal transduction.