PTPRO-mediated autophagy prevents hepatosteatosis and tumorigenesis.

Wenjie Zhang,Xiaochen Wang,Jie Ji,Yin Yin,Ke Wang,Runqiu Jiang,Beicheng Sun,Xingxu Huang,Jiajie Hou,Lei Deng

doi:10.18632/oncotarget.3353

Abstract

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.

Highlights

Nonalcoholic fatty liver disease (NAFLD), the hepatic consequence of metabolic syndrome, is the most common cause of chronic liver disease in both industrialized and developing nations [1,2,3]
phosphatase receptor type O (PTPRO) deletion in hepatocytes exacerbates steatosis and promotes tumorigenesis To investigate whether PTPRO contributes to steatosis and tumorigenesis, we used a non-alcoholic steatohepatitis (NASH)-hepatocellular carcinoma (HCC) animal model to monitor progression from obesity to HCC according to the method reported by Park [24]
high-fat diet (HFD)-fed mice gained more weight compared to the later fed them either normal chow (LFD)-fed mice and there was no difference between WT and ptpro−/− animals (Supplementary Figure S1A)

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD), the hepatic consequence of metabolic syndrome, is the most common cause of chronic liver disease in both industrialized and developing nations [1,2,3]. NAFLD represents a continuum of disorders that range from simple steatosis to non-alcoholic steatohepatitis (NASH) to cirrhosis, which are generally considered irreversible and increase the prevalence of hepatocellular carcinoma [4, 5]. Autophagy has been shown to play an important role in many critical biological processes during periods of starvation, but has emerged as a primary quality control mechanism necessary for the maintenance of cellular homeostasis [8, 9]. Defective autophagy has been shown to result in enhanced chromosomal instability, with failure to degrade damaged cellular components contributing to promotion of the development of a large number of diseases, including hepatocellular carcinoma [12]. HFDfed mice have been shown to exhibit defective hepatic autophagic function, which is reflected by decreases in the LC3-II/I ratio and increases in p62 expression [12]

Methods

Results

Conclusion