title: Expression and function of methylthioadenosine phosphorylase in chronic liver disease.
abstract: To study expression and function of methylthioadenosine phosphorylase (MTAP), the rate-limiting enzyme in the methionine and adenine salvage pathway, in chronic liver disease.
  
  
  METHODS
  MTAP expression was analyzed by qRT-PCR, Western blot and immunohistochemical analysis. Levels of MTA were determined by liquid chromatography-tandem mass spectrometry.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
authors: Barbara
authors: B
authors: Czech
authors: Katja
authors: K
authors: Dettmer
authors: Daniela
authors: D
authors: Valletta
authors: Michael
authors: M
authors: Saugspier
authors: Andreas
authors: A
authors: Koch
authors: Axel P
authors: AP
authors: Stevens
authors: Wolfgang E
authors: WE
authors: Thasler
authors: Martina
authors: M
authors: Müller
authors: Peter J
authors: PJ
authors: Oefner
authors: Anja-Katrin
authors: AK
authors: Bosserhoff
authors: Claus
authors: C
authors: Hellerbrand
mesh_terms: D000225:Adenine / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002908:Chronic Disease; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000201:enzymology* / Q000473:pathology; D022781:Hepatocytes / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D008103:Liver Cirrhosis / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008715:Methionine / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000077022:Survivin; D013873:Thionucleotides / Q000378:metabolism*
chemical_list: C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D000077022:Survivin; D013873:Thionucleotides; D008715:Methionine; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D000225:Adenine