PTPRO-mediated Autophagy Inhibits Liver Steatosis And Tumor Formation

Background:Obesity induced NASH(Non-alcoholic steatohepatitis)could significantly promote hepatocellular carcinoma(HCC)development.Protein tyrosine phosphatase receptor type O(PTPRO)was recently identified as a tumor suppressor,but little is known about its role in NASH.Methods:Wild-type(WT)and ptpro-/-mice were fed a high-fat diet(HFD)for another 16 weeks after diethylnitrosamine(DEN)injection to induce NASH.Serum ALT and AST activity were uesd to evaluated liver function.H&E and oil red-O staining were employed to examine the degree of hepatic steatosis.Liver TG,serum TG and insulin were also examined.Lipid storage gene expression involved in lipogenesis and ?-oxidation in the liver were analyzed by real-time PCR.Cell proliferation and apoptosis were evaluated by Edu and terminal deoxynucleotidyl transferase mediated dUTP nick end labeling(TUNEL),which were also confirmed by detecting Cyclin D1 and anti-apoptotic protein Bcl-2 expression.Moreover,tumor number and size were recorded after 30 weeks feeding.Results: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?-oxidation-related genes.Enhanced apoptosis and compensatory proliferation of hepatocytes were also observed in ptpro-/-mice.Moreover,ptpro-/-mice presented larger tumor number and size after 30 weeks feeding.Conclusion:As a tumor supressor,PTPRO deletion promotes lipid and insulin accumulation as well as tumor formation.Background:Autophagy plays a critical role in the progression of nonalcoholic steatohepatitis(NASH)and hepatocellular carcinoma(HCC).We have found that PTPRO deletion promoted hepatosteatosis and tumorigenesis.But,the underlying mechanism is still elusive.Here,we investigated the mechanism of PTPRO preventing hepatosteatosis.Methods:Wild type(WT)and ptpro-/-mice were fed a high-fat diet(HFD)to induce NASH.Western blot analyses were used to evaluate the expression levels of autophagy-related markers LC3I/II and p62.Isolated mouse hepatocytes were treated with insulin in vitro.Clinical patients with benign liver conditions undergoing liver surgery were included in our study.Results:Ptpro-/-mice exhibited severe autophagy deficiency compared with WT littermates.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.Conclusion:These data indicate that PTPRO regulates insulin and lipid metabolism via the PI3K/AKT/MDM4/MDM2/p53 axis by affecting autophagy.