Z Gastroenterol 2013; 51 - P_1_11
DOI: 10.1055/s-0032-1331911

Functional effects of methylthioadenosine phosphorylase (MTAP) expression in chronic liver disease

B Czech 1, D Valletta 1, K Dettmer 2, M Müller 1, A Bosserhoff 3, P Oefner 2, C Hellerbrand 1
  • 1University Hospital Regensburg, Department of Internal Medicine I, Regensburg, Germany
  • 2University Regensburg, Institute of Functional Genomics, University Regensburg, Germany, Regensburg, Germany
  • 3University Regensburg, Institute of Pathology, Regensburg, Germany

The polyamine metabolic pathway has been implicated in the pathogenesis of chronic liver disease. 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 in chronic liver disease.

Methods and Results: MTAP mRNA and protein were reduced in murine fibrosis models and in patients with chronic liver disease, which was accompanied by increased hepatic MTA levels as assessed by liquid chromatography tandem mass spectrometry. Immunohistochemical analysis revealed downregulated MTAP expression in hepatocytes, while hepatic stellate cells (HSCs) showed a strong MTAP immunosignal in cirrhotic livers. In line with this, MTAP expression rises during in vitro HSC activation. However and notably, intracellular MTA levels as well as MTA-release into the supernatant of activated human HSCs were significantly higher than in primary human hepatocytes in vitro, and we found a significant correlation between MTA-levels and the expression of collagen I in diseased human liver tissue. Together, these findings indicate activated HSCs as the main hepatic source of MTA in chronically diseased livers. Conversely, MTA stimulation of activated HSCs induced activation of NFkappaB and resistance against apoptosis. In accordance, MTAP suppression by siRNA induced MTA levels and the resistance against apoptosis while overexpression of MTAP reduced MTA levels and apoptosis resistance in HSCs. As underlying mechanisms of the anti-apoptotic effect of MTA we identified survivin, which is a known NFkappaB target gene. This anti-apoptotic factor was dose-dependently induced in HSCs by MTA while inhibition of survivin abolished the anti-apoptotic effect of MTA on HSCs.

Conclusion: In this study we identified MTAP mediated regulation of MTA as a new link between polyamine metabolism and NFkappaB mediated effects on apoptosis in HSCs. Recently, we revealed MTAP as tumor-suppressor in HCC. Together these findings suggest MTAP or MTAP inducing factors, respectively, as attractive therapeutic targets to inhibit the progression of chronic liver disease.