PPARγ induces NEDD4 gene expression to promote autophagy and insulin action

The E3 ubiquitin ligase neural precursor cell-expressed developmentally down-regulated protein 4 (NEDD4) plays a crucial role in governing a number of signaling pathways, including insulin and autophagy signaling. However, the molecular mechanism by which NEDD4 gene is transcriptionally regulated has not been fully elucidated. Here, we reported that NEDD4 mRNA and protein levels were increased by peroxisome proliferator-activated receptor-gamma (PPARgamma) in HepG2 hepatocytes. PPARgamma antagonist GW9662 abolished thiazolidinedione (TZD)-induced NEDD4 expression. ChIP and luciferase reporter assays showed that PPARgamma directly bound to the potential PPAR-responsive elements (PPREs) within the promoter region of the human NEDD4 gene. In addition, TZDs increased Akt phosphorylation and glucose uptake, which were abrogated through NEDD4 depletion. Furthermore, we showed that NEDD4-mediated autophagy induction and Akt phosphorylation were suppressed by oleic acid and high glucose treatment, activation of PPARgamma successfully prevented this suppression. In conclusion, these results suggest that PPARgamma plays a novel role in linking glucose metabolism and protein homeostasis through NEDD4-mediated effects on the autophagy machinery.