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PTPRO-mediated autophagy prevents hepatosteatosis and tumorigenesis.

Zhang W, Hou J, Wang X, Jiang R, Yin Y, Ji J, Deng L, Huang X, Wang K, Sun B - Oncotarget (2015)

Bottom Line: PTPRO deletion also promoted the induction of lipogenic target genes and decreases in β-oxidation-related genes.Inhibition of AKT restored autophagy and p53 accumulation in hepatocytes, indicating that AKT acts upstream of p53.Importantly, the expression of PTPRO was much decreased in human steatohepatitis, which was associated with increased p62 accumulation.

View Article: PubMed Central - PubMed

Affiliation: Liver Transplantation Center of The First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China.

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.

No MeSH data available.


Related in: MedlinePlus

PTPRO deletion in hepatocytes exacerbates steatosis and promotes tumorigenesis(A) DEN was injected intraperitoneally (i.p.) into 14-day-old mice (WT and ptpro−/−). Four weeks later, the mice were fed a LFD or HFD for a further 16 weeks (n = 6 per group) or 24 weeks (n = 4 per group). (B) ROS levels were measured in LFD and HFD mouse specimens. (C) Liver sections of LFD and HFD mice were stained with H&E (original magnification, x200). (D) Liver sections of LFD and HFD mice were stained with Oil-Red O (original magnification, x200). (E) The levels of Serum aminotransferases were measured (n = 6 per group). (F1) Liver from 30-week-old DEN-treated mice. Tumorigenesis was investigated in WT and ptpro−/− mice. (F2) Comparison of tumor multiplicity in male WT and ptpro−/− mice (n = 4 per group). All data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001.
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Figure 1: PTPRO deletion in hepatocytes exacerbates steatosis and promotes tumorigenesis(A) DEN was injected intraperitoneally (i.p.) into 14-day-old mice (WT and ptpro−/−). Four weeks later, the mice were fed a LFD or HFD for a further 16 weeks (n = 6 per group) or 24 weeks (n = 4 per group). (B) ROS levels were measured in LFD and HFD mouse specimens. (C) Liver sections of LFD and HFD mice were stained with H&E (original magnification, x200). (D) Liver sections of LFD and HFD mice were stained with Oil-Red O (original magnification, x200). (E) The levels of Serum aminotransferases were measured (n = 6 per group). (F1) Liver from 30-week-old DEN-treated mice. Tumorigenesis was investigated in WT and ptpro−/− mice. (F2) Comparison of tumor multiplicity in male WT and ptpro−/− mice (n = 4 per group). All data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001.

Mentions: To investigate whether PTPRO contributes to steatosis and tumorigenesis, we used a NASH-HCC animal model to monitor progression from obesity to HCC according to the method reported by Park [24]. Briefly, as shown in Figure 1A, on postnatal day 14 we injected DEN (25 mg/kg) into male mice and 4 weeks later fed them either normal chow (LFD) or a high-fat diet (HFD) until sacrifice (22 weeks). The other mice kept on feeding until the initiation of tumor formation. and then sacrificed (30 weeks). As expected, HFD-fed mice gained more weight compared to the LFD-fed mice and there was no difference between WT and ptpro−/− animals (Supplementary Figure S1A). Since ROS normally increase during development of NASH, we examined ROS accumulation in WT and ptpro−/− mice fed a LFD or HFD. Obesity significantly increased ROS accumulation (***P < 0.001). Additionally, in ptpro−/− mice, more severe ROS production was induced (Figure 1B). Based on these phenotypes, H&E and oil red-O staining were employed to examine the degree of hepatic steatosis. Although ptpro−/− mice did not show an obvious increase in hepatocellular ballooning (Figure 1C), it was able to promote fat droplet accumulation in LFD-fed groups (Figure 1D). In contrast, ptpro−/−-HFD-fed mice had significantly worse HFD-induced hepatic lipid accumulation. Moreover, significantly elevated serum ALT and AST activity indicated that severe hepatic injury had occurred in obese mice. Liver damage in ptpro−/− mice was markedly more severe compared to WT mice (Figure 1E).


PTPRO-mediated autophagy prevents hepatosteatosis and tumorigenesis.

Zhang W, Hou J, Wang X, Jiang R, Yin Y, Ji J, Deng L, Huang X, Wang K, Sun B - Oncotarget (2015)

PTPRO deletion in hepatocytes exacerbates steatosis and promotes tumorigenesis(A) DEN was injected intraperitoneally (i.p.) into 14-day-old mice (WT and ptpro−/−). Four weeks later, the mice were fed a LFD or HFD for a further 16 weeks (n = 6 per group) or 24 weeks (n = 4 per group). (B) ROS levels were measured in LFD and HFD mouse specimens. (C) Liver sections of LFD and HFD mice were stained with H&E (original magnification, x200). (D) Liver sections of LFD and HFD mice were stained with Oil-Red O (original magnification, x200). (E) The levels of Serum aminotransferases were measured (n = 6 per group). (F1) Liver from 30-week-old DEN-treated mice. Tumorigenesis was investigated in WT and ptpro−/− mice. (F2) Comparison of tumor multiplicity in male WT and ptpro−/− mice (n = 4 per group). All data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496227&req=5

Figure 1: PTPRO deletion in hepatocytes exacerbates steatosis and promotes tumorigenesis(A) DEN was injected intraperitoneally (i.p.) into 14-day-old mice (WT and ptpro−/−). Four weeks later, the mice were fed a LFD or HFD for a further 16 weeks (n = 6 per group) or 24 weeks (n = 4 per group). (B) ROS levels were measured in LFD and HFD mouse specimens. (C) Liver sections of LFD and HFD mice were stained with H&E (original magnification, x200). (D) Liver sections of LFD and HFD mice were stained with Oil-Red O (original magnification, x200). (E) The levels of Serum aminotransferases were measured (n = 6 per group). (F1) Liver from 30-week-old DEN-treated mice. Tumorigenesis was investigated in WT and ptpro−/− mice. (F2) Comparison of tumor multiplicity in male WT and ptpro−/− mice (n = 4 per group). All data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001.
Mentions: To investigate whether PTPRO contributes to steatosis and tumorigenesis, we used a NASH-HCC animal model to monitor progression from obesity to HCC according to the method reported by Park [24]. Briefly, as shown in Figure 1A, on postnatal day 14 we injected DEN (25 mg/kg) into male mice and 4 weeks later fed them either normal chow (LFD) or a high-fat diet (HFD) until sacrifice (22 weeks). The other mice kept on feeding until the initiation of tumor formation. and then sacrificed (30 weeks). As expected, HFD-fed mice gained more weight compared to the LFD-fed mice and there was no difference between WT and ptpro−/− animals (Supplementary Figure S1A). Since ROS normally increase during development of NASH, we examined ROS accumulation in WT and ptpro−/− mice fed a LFD or HFD. Obesity significantly increased ROS accumulation (***P < 0.001). Additionally, in ptpro−/− mice, more severe ROS production was induced (Figure 1B). Based on these phenotypes, H&E and oil red-O staining were employed to examine the degree of hepatic steatosis. Although ptpro−/− mice did not show an obvious increase in hepatocellular ballooning (Figure 1C), it was able to promote fat droplet accumulation in LFD-fed groups (Figure 1D). In contrast, ptpro−/−-HFD-fed mice had significantly worse HFD-induced hepatic lipid accumulation. Moreover, significantly elevated serum ALT and AST activity indicated that severe hepatic injury had occurred in obese mice. Liver damage in ptpro−/− mice was markedly more severe compared to WT mice (Figure 1E).

Bottom Line: PTPRO deletion also promoted the induction of lipogenic target genes and decreases in β-oxidation-related genes.Inhibition of AKT restored autophagy and p53 accumulation in hepatocytes, indicating that AKT acts upstream of p53.Importantly, the expression of PTPRO was much decreased in human steatohepatitis, which was associated with increased p62 accumulation.

View Article: PubMed Central - PubMed

Affiliation: Liver Transplantation Center of The First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China.

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.

No MeSH data available.


Related in: MedlinePlus