Hepatocyte PRMT1 protects from alcohol induced liver injury by modulating oxidative stress responses

Abstract Protein Arginine methyltransferase 1 (PRMT1) is the main enzyme of cellular arginine methylation. Previously we found that PRMT1 activity in the liver is altered after alcohol exposure resulting in epigenetic changes. To determine the impact of these PRMT1 changes on the liver’s response to...

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Autores principales:	Jie Zhao, Abby Adams, Steven A. Weinman, Irina Tikhanovich
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/40094f9e46ee4b0bb11bea403a428a16
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spelling	oai:doaj.org-article:40094f9e46ee4b0bb11bea403a428a162021-12-02T15:08:19ZHepatocyte PRMT1 protects from alcohol induced liver injury by modulating oxidative stress responses10.1038/s41598-019-45585-22045-2322https://doaj.org/article/40094f9e46ee4b0bb11bea403a428a162019-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-45585-2https://doaj.org/toc/2045-2322Abstract Protein Arginine methyltransferase 1 (PRMT1) is the main enzyme of cellular arginine methylation. Previously we found that PRMT1 activity in the liver is altered after alcohol exposure resulting in epigenetic changes. To determine the impact of these PRMT1 changes on the liver’s response to alcohol, we induced a hepatocyte specific PRMT1 knockout using AAV mediated Cre delivery in mice fed either alcohol or control Lieber-DeCarli liquid diet. We found that in alcohol fed mice, PRMT1 prevents oxidative stress and promotes hepatocyte survival. PRMT1 knockout in alcohol fed mice resulted in a dramatic increase in hepatocyte death, inflammation and fibrosis. Additionally, we found that alcohol promotes PRMT1 dephosphorylation at S297. Phosphorylation at this site is necessary for PRMT1-dependent protein arginine methylation. PRMT1 S297A, a dephosphorylation mimic of PRMT1 had reduced ability to promote gene expression of pro-inflammatory cytokines, pro-apoptotic genes BIM and TRAIL and expression of a suppressor of hepatocyte proliferation, Hnf4α. On the other hand, several functions of PRMT1 were phosphorylation-independent, including expression of oxidative stress response genes, Sod1, Sod2 and others. In vitro, both wild type and S297A PRMT1 protected hepatocytes from oxidative stress induced apoptosis, however S297D phosphorylation mimic PRMT1 promoted cell death. Taken together these data suggest that PRMT1 is an essential factor of liver adaptation to alcohol; alcohol-induced dephosphorylation shifts PRMT1 toward a less pro-inflammatory, more pro-proliferative and pro-survival form.Jie ZhaoAbby AdamsSteven A. WeinmanIrina TikhanovichNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-15 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jie Zhao Abby Adams Steven A. Weinman Irina Tikhanovich Hepatocyte PRMT1 protects from alcohol induced liver injury by modulating oxidative stress responses
description	Abstract Protein Arginine methyltransferase 1 (PRMT1) is the main enzyme of cellular arginine methylation. Previously we found that PRMT1 activity in the liver is altered after alcohol exposure resulting in epigenetic changes. To determine the impact of these PRMT1 changes on the liver’s response to alcohol, we induced a hepatocyte specific PRMT1 knockout using AAV mediated Cre delivery in mice fed either alcohol or control Lieber-DeCarli liquid diet. We found that in alcohol fed mice, PRMT1 prevents oxidative stress and promotes hepatocyte survival. PRMT1 knockout in alcohol fed mice resulted in a dramatic increase in hepatocyte death, inflammation and fibrosis. Additionally, we found that alcohol promotes PRMT1 dephosphorylation at S297. Phosphorylation at this site is necessary for PRMT1-dependent protein arginine methylation. PRMT1 S297A, a dephosphorylation mimic of PRMT1 had reduced ability to promote gene expression of pro-inflammatory cytokines, pro-apoptotic genes BIM and TRAIL and expression of a suppressor of hepatocyte proliferation, Hnf4α. On the other hand, several functions of PRMT1 were phosphorylation-independent, including expression of oxidative stress response genes, Sod1, Sod2 and others. In vitro, both wild type and S297A PRMT1 protected hepatocytes from oxidative stress induced apoptosis, however S297D phosphorylation mimic PRMT1 promoted cell death. Taken together these data suggest that PRMT1 is an essential factor of liver adaptation to alcohol; alcohol-induced dephosphorylation shifts PRMT1 toward a less pro-inflammatory, more pro-proliferative and pro-survival form.
format	article
author	Jie Zhao Abby Adams Steven A. Weinman Irina Tikhanovich
author_facet	Jie Zhao Abby Adams Steven A. Weinman Irina Tikhanovich
author_sort	Jie Zhao
title	Hepatocyte PRMT1 protects from alcohol induced liver injury by modulating oxidative stress responses
title_short	Hepatocyte PRMT1 protects from alcohol induced liver injury by modulating oxidative stress responses
title_full	Hepatocyte PRMT1 protects from alcohol induced liver injury by modulating oxidative stress responses
title_fullStr	Hepatocyte PRMT1 protects from alcohol induced liver injury by modulating oxidative stress responses
title_full_unstemmed	Hepatocyte PRMT1 protects from alcohol induced liver injury by modulating oxidative stress responses
title_sort	hepatocyte prmt1 protects from alcohol induced liver injury by modulating oxidative stress responses
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/40094f9e46ee4b0bb11bea403a428a16
work_keys_str_mv	AT jiezhao hepatocyteprmt1protectsfromalcoholinducedliverinjurybymodulatingoxidativestressresponses AT abbyadams hepatocyteprmt1protectsfromalcoholinducedliverinjurybymodulatingoxidativestressresponses AT stevenaweinman hepatocyteprmt1protectsfromalcoholinducedliverinjurybymodulatingoxidativestressresponses AT irinatikhanovich hepatocyteprmt1protectsfromalcoholinducedliverinjurybymodulatingoxidativestressresponses
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Hepatocyte PRMT1 protects from alcohol induced liver injury by modulating oxidative stress responses

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