Journal
ONCOTARGET
Volume 6, Issue 11, Pages 9420-9433Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.3353
Keywords
PTPRO; autophagy; AKT; p53; nonalcoholic steatohepatitis
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Funding
- National Natural Science Foundation for Distinguished Young Scholars [81225017]
- National Basic Research Program of China [2012CB910800]
- National Natural Science Foundation [81302106, 81201528]
- program for Development of Innovative Research Team in the First Affiliated Hospital of NJMU
- Priority Academic Program of Jiangsu Higher Education Institutions
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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 beta-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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