PTPRO-mediated autophagy prevents hepatosteatosis and tumorigenesis
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Wenjie Zhang1,*, Jiajie Hou1,*, Xiaochen Wang1, Runqiu Jiang1, Yin Yin1, Jie Ji1, Lei Deng1,2, Xingxu Huang2, Ke Wang1, Beicheng Sun1
1Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China
2MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, P.R. China
*These authors have contributed equally to this work
Beicheng Sun, e-mail: [email protected]
Keywords: PTPRO, autophagy, AKT, p53, nonalcoholic steatohepatitis
Received: December 02, 2014 Accepted: February 10, 2015 Published: March 20, 2015
Autophagy plays a critical role in the progression of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Protein tyrosine phosphatase receptor type O (PTPRO) was recently identified as a tumor suppressor, but little is known about its role in NASH. Here, we investigated the role of PTPRO-dependent autophagy in insulin resistance, lipid metabolism, and hepatocarcinogenesis. Wild-type (WT) and ptpro−/− mice were fed a high-fat diet (HFD) for another 16 weeks after diethylnitrosamine (DEN) injection to induce NASH. Ptpro−/− mice exhibited severe liver injury, insulin resistance, hepatosteatosis and autophagy deficiency compared with WT littermates. PTPRO deletion also promoted the induction of lipogenic target genes and decreases in β-oxidation-related genes. Increased activation of AKT and accumulation of cytoplasmic p53 was detected in ptpro−/− mice, which in combination repressed autophagy. Intriguingly, hyperinsulinemia involving AKT activation was also exacerbated in HFD-fed mice due to PTPRO deletion. Activation of AKT induced stabilization of the MDMX/MDM2 heterocomplex, thus promoting p53 accumulation in the cytoplasm. Inhibition of AKT restored autophagy and p53 accumulation in hepatocytes, indicating that AKT acts upstream of p53. Due to hyperinsulinemia and autophagy deficiency, a HFD could aggravate steatohepatitis in ptpro−/− mice. Importantly, the expression of PTPRO was much decreased in human steatohepatitis, which was associated with increased p62 accumulation. Together, these data indicate that PTPRO regulates insulin and lipid metabolism via the PI3K/Akt/MDM4/MDM2/P53 axis by affecting autophagy.
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