Expression and function of methylthioadenosine phosphorylase in chronic liver disease.

<h4>Unlabelled</h4>To study expression and function of methylthioadenosine phosphorylase (MTAP), the rate-limiting enzyme in the methionine and adenine salvage pathway, in chronic liver disease.<h4>Design</h4>MTAP expression was analyzed by qRT-PCR, Western blot and immunohis...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Barbara Czech, Katja Dettmer, Daniela Valletta, Michael Saugspier, Andreas Koch, Axel P Stevens, Wolfgang E Thasler, Martina Müller, Peter J Oefner, Anja-Katrin Bosserhoff, Claus Hellerbrand
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/99fce861bc804cf8adaae5c0e4154629
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:99fce861bc804cf8adaae5c0e4154629
record_format	dspace
spelling	oai:doaj.org-article:99fce861bc804cf8adaae5c0e41546292021-11-18T08:43:12ZExpression and function of methylthioadenosine phosphorylase in chronic liver disease.1932-620310.1371/journal.pone.0080703https://doaj.org/article/99fce861bc804cf8adaae5c0e41546292013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24324622/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Unlabelled</h4>To study expression and function of methylthioadenosine phosphorylase (MTAP), the rate-limiting enzyme in the methionine and adenine salvage pathway, in chronic liver disease.<h4>Design</h4>MTAP expression was analyzed by qRT-PCR, Western blot and immunohistochemical analysis. Levels of MTA were determined by liquid chromatography-tandem mass spectrometry.<h4>Results</h4>MTAP was downregulated in hepatocytes in murine fibrosis models and in patients with chronic liver disease, leading to a concomitant increase in MTA levels. In contrast, activated hepatic stellate cells (HSCs) showed strong MTAP expression in cirrhotic livers. However, also MTA levels in activated HSCs were significantly higher than in hepatocytes, and there was a significant correlation between MTA levels and collagen expression in diseased human liver tissue indicating that activated HSCs significantly contribute to elevated MTA in diseased livers. MTAP suppression by siRNA resulted in increased MTA levels, NFκB activation and apoptosis resistance, while overexpression of MTAP caused the opposite effects in HSCs. The anti-apoptotic effect of low MTAP expression and high MTA levels, respectively, was mediated by induced expression of survivin, while inhibition of survivin abolished the anti-apoptotic effect of MTA on HSCs. Treatment with a DNA demethylating agent induced MTAP and reduced survivin expression, while oxidative stress reduced MTAP levels but enhanced survivin expression in HSCs.<h4>Conclusion</h4>MTAP mediated regulation of MTA links polyamine metabolism with NFκB activation and apoptosis in HSCs. MTAP and MTAP modulating mechanisms appear as promising prognostic markers and therapeutic targets for hepatic fibrosis.Barbara CzechKatja DettmerDaniela VallettaMichael SaugspierAndreas KochAxel P StevensWolfgang E ThaslerMartina MüllerPeter J OefnerAnja-Katrin BosserhoffClaus HellerbrandPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 12, p e80703 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Barbara Czech Katja Dettmer Daniela Valletta Michael Saugspier Andreas Koch Axel P Stevens Wolfgang E Thasler Martina Müller Peter J Oefner Anja-Katrin Bosserhoff Claus Hellerbrand Expression and function of methylthioadenosine phosphorylase in chronic liver disease.
description	<h4>Unlabelled</h4>To study expression and function of methylthioadenosine phosphorylase (MTAP), the rate-limiting enzyme in the methionine and adenine salvage pathway, in chronic liver disease.<h4>Design</h4>MTAP expression was analyzed by qRT-PCR, Western blot and immunohistochemical analysis. Levels of MTA were determined by liquid chromatography-tandem mass spectrometry.<h4>Results</h4>MTAP was downregulated in hepatocytes in murine fibrosis models and in patients with chronic liver disease, leading to a concomitant increase in MTA levels. In contrast, activated hepatic stellate cells (HSCs) showed strong MTAP expression in cirrhotic livers. However, also MTA levels in activated HSCs were significantly higher than in hepatocytes, and there was a significant correlation between MTA levels and collagen expression in diseased human liver tissue indicating that activated HSCs significantly contribute to elevated MTA in diseased livers. MTAP suppression by siRNA resulted in increased MTA levels, NFκB activation and apoptosis resistance, while overexpression of MTAP caused the opposite effects in HSCs. The anti-apoptotic effect of low MTAP expression and high MTA levels, respectively, was mediated by induced expression of survivin, while inhibition of survivin abolished the anti-apoptotic effect of MTA on HSCs. Treatment with a DNA demethylating agent induced MTAP and reduced survivin expression, while oxidative stress reduced MTAP levels but enhanced survivin expression in HSCs.<h4>Conclusion</h4>MTAP mediated regulation of MTA links polyamine metabolism with NFκB activation and apoptosis in HSCs. MTAP and MTAP modulating mechanisms appear as promising prognostic markers and therapeutic targets for hepatic fibrosis.
format	article
author	Barbara Czech Katja Dettmer Daniela Valletta Michael Saugspier Andreas Koch Axel P Stevens Wolfgang E Thasler Martina Müller Peter J Oefner Anja-Katrin Bosserhoff Claus Hellerbrand
author_facet	Barbara Czech Katja Dettmer Daniela Valletta Michael Saugspier Andreas Koch Axel P Stevens Wolfgang E Thasler Martina Müller Peter J Oefner Anja-Katrin Bosserhoff Claus Hellerbrand
author_sort	Barbara Czech
title	Expression and function of methylthioadenosine phosphorylase in chronic liver disease.
title_short	Expression and function of methylthioadenosine phosphorylase in chronic liver disease.
title_full	Expression and function of methylthioadenosine phosphorylase in chronic liver disease.
title_fullStr	Expression and function of methylthioadenosine phosphorylase in chronic liver disease.
title_full_unstemmed	Expression and function of methylthioadenosine phosphorylase in chronic liver disease.
title_sort	expression and function of methylthioadenosine phosphorylase in chronic liver disease.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/99fce861bc804cf8adaae5c0e4154629
work_keys_str_mv	AT barbaraczech expressionandfunctionofmethylthioadenosinephosphorylaseinchronicliverdisease AT katjadettmer expressionandfunctionofmethylthioadenosinephosphorylaseinchronicliverdisease AT danielavalletta expressionandfunctionofmethylthioadenosinephosphorylaseinchronicliverdisease AT michaelsaugspier expressionandfunctionofmethylthioadenosinephosphorylaseinchronicliverdisease AT andreaskoch expressionandfunctionofmethylthioadenosinephosphorylaseinchronicliverdisease AT axelpstevens expressionandfunctionofmethylthioadenosinephosphorylaseinchronicliverdisease AT wolfgangethasler expressionandfunctionofmethylthioadenosinephosphorylaseinchronicliverdisease AT martinamuller expressionandfunctionofmethylthioadenosinephosphorylaseinchronicliverdisease AT peterjoefner expressionandfunctionofmethylthioadenosinephosphorylaseinchronicliverdisease AT anjakatrinbosserhoff expressionandfunctionofmethylthioadenosinephosphorylaseinchronicliverdisease AT claushellerbrand expressionandfunctionofmethylthioadenosinephosphorylaseinchronicliverdisease
_version_	1718421398007840768

Expression and function of methylthioadenosine phosphorylase in chronic liver disease.

Ejemplares similares