Z Gastroenterol 2012; 50 - P1_07
DOI: 10.1055/s-0031-1295737

Downregulation of methylthioadenosine phosphorylase (MTAP) expression in chronic liver disease promotes hepatic inflammation and fibrosis

B Czech 1, D Valletta 1, M Saugspier 1, K Dettmer 2, A Stevens 2, C Dorn 1, TS Weiss 3, A Bosserhoff 4, P Oefner 2, C Hellerbrand 1
  • 1Department of Internal Medicine I, University Hospital Regensburg, Regensburg
  • 2Institute of Functional Genomics, University of Regensburg, Regensburg
  • 3Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Regensburg, Regensburg
  • 4Institut für Pathologie, Regensburg

Methylthioadenosine phosphorylase (MTAP) the rate-limiting enzyme in the methionine and adenine salvage pathway catalyzes the phosphorylation of 5´-deoxy–5´-(methylthio)adenosine (MTA) which is a by-product of polyamine synthesis.

The aim of this study was to assess MTAP expression and function during the progression of chronic liver disease.

Methods and Results: MTAP mRNA and protein were reduced in the murine bile-duct ligation model and in patients with chronic liver disease, which was accompanied by increased hepatic and serum levels of MTA as assessed by liquid chromatography tandem mass spectrometry. In vitro stimulation of primary human hepatocytes (PHH) with MTA (in concentrations found in diseased livers; up to 5 pmol/mg) induced a dose dependent induction of proinflammatory gene expression. Further, in hepatic stellate cells (HSC) MTA-stimulation induced the activation of NFkappaB, profibrogenic gene expression, proliferation and resistance against apoptosis. In accordance, downregulation of MTAP expression in HSC by siRNA induced the resistance against apoptosis and pro-fibrogenic gene expression. In search for the mechanisms regulating MTAP expression in HSC, we found that hypoxia inhibits MTAP mRNA und protein. Hypoxia was associated with formation of reactive oxygen species (ROS), and also chemically induced ROS-formation reduced MTAP expression, while ROS-scavengers abolished the hypoxia mediated downregulation in activated HSC. Notably, intracellular MTA levels as well as MTA-release into the supernatant of activated HSCs were significantly higher than in PHH, indicating activated HSC as major hepatic source of MTA.

Conclusion: Reduced MTAP expression in chronic liver disease promotes hepatic inflammation and fibrosis via accumulation of MTA. Interfering with (the mechanisms leading to) the downregulation of MTAP appears as novel therapeutic strategy to prevent the progression of chronic liver disease.