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PPAR γ induces NEDD 4 gene expression to promote autophagy and insulin action
Author(s) -
Liu Jia,
Yao Qinyu,
Xiao Lei,
Ma Wen,
Li Fan,
Lai Baochang,
Wang Nanping
Publication year - 2020
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.15042
Subject(s) - nedd4 , peroxisome proliferator activated receptor , ubiquitin ligase , microbiology and biotechnology , protein kinase b , autophagy , mtorc1 , phosphorylation , chemistry , signal transduction , reporter gene , pi3k/akt/mtor pathway , biology , ubiquitin , receptor , gene expression , biochemistry , gene , apoptosis
The E3 ubiquitin ligase neural precursor cell‐expressed developmentally down‐regulated protein 4 ( NEDD 4) plays a crucial role in governing a number of signaling pathways, including insulin and autophagy signaling. However, the molecular mechanism by which NEDD 4 gene is transcriptionally regulated has not been fully elucidated. Here, we reported that NEDD 4 mRNA and protein levels were increased by peroxisome proliferator‐activated receptor‐γ ( PPAR γ) in HepG2 hepatocytes. PPAR γ antagonist GW 9662 abolished thiazolidinedione (TZD)‐induced NEDD 4 expression. Ch IP and luciferase reporter assays showed that PPAR γ directly bound to the potential PPAR ‐responsive elements ( PPRE s) within the promoter region of the human NEDD 4 gene. In addition, TZD s increased Akt phosphorylation and glucose uptake, which were abrogated through NEDD 4 depletion. Furthermore, we showed that NEDD 4‐mediated autophagy induction and Akt phosphorylation were suppressed by oleic acid and high glucose treatment, activation of PPAR γ successfully prevented this suppression. In conclusion, these results suggest that PPAR γ plays a novel role in linking glucose metabolism and protein homeostasis through NEDD 4‐mediated effects on the autophagy machinery.