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PTPRO-mediated autophagy prevents hepatosteatosis and tumorigenesis

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...

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Autores principales: Zhang, Wenjie, Hou, Jiajie, Wang, Xiaochen, Jiang, Runqiu, Yin, Yin, Ji, Jie, Deng, Lei, Huang, Xingxu, Wang, Ke, Sun, Beicheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496227/
https://www.ncbi.nlm.nih.gov/pubmed/25826083
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author Zhang, Wenjie
Hou, Jiajie
Wang, Xiaochen
Jiang, Runqiu
Yin, Yin
Ji, Jie
Deng, Lei
Huang, Xingxu
Wang, Ke
Sun, Beicheng
author_facet Zhang, Wenjie
Hou, Jiajie
Wang, Xiaochen
Jiang, Runqiu
Yin, Yin
Ji, Jie
Deng, Lei
Huang, Xingxu
Wang, Ke
Sun, Beicheng
author_sort Zhang, Wenjie
collection PubMed
description 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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spelling pubmed-44962272015-07-10 PTPRO-mediated autophagy prevents hepatosteatosis and tumorigenesis Zhang, Wenjie Hou, Jiajie Wang, Xiaochen Jiang, Runqiu Yin, Yin Ji, Jie Deng, Lei Huang, Xingxu Wang, Ke Sun, Beicheng Oncotarget Research Paper 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. Impact Journals LLC 2015-03-20 /pmc/articles/PMC4496227/ /pubmed/25826083 Text en Copyright: © 2015 Zhang et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Zhang, Wenjie
Hou, Jiajie
Wang, Xiaochen
Jiang, Runqiu
Yin, Yin
Ji, Jie
Deng, Lei
Huang, Xingxu
Wang, Ke
Sun, Beicheng
PTPRO-mediated autophagy prevents hepatosteatosis and tumorigenesis
title PTPRO-mediated autophagy prevents hepatosteatosis and tumorigenesis
title_full PTPRO-mediated autophagy prevents hepatosteatosis and tumorigenesis
title_fullStr PTPRO-mediated autophagy prevents hepatosteatosis and tumorigenesis
title_full_unstemmed PTPRO-mediated autophagy prevents hepatosteatosis and tumorigenesis
title_short PTPRO-mediated autophagy prevents hepatosteatosis and tumorigenesis
title_sort ptpro-mediated autophagy prevents hepatosteatosis and tumorigenesis
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496227/
https://www.ncbi.nlm.nih.gov/pubmed/25826083
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