Z Gastroenterol 2011; 49 - P1_10
DOI: 10.1055/s-0030-1269460

Expression and function of methylthioadenosine phosphorylase (MTAP) in chronic liver disease

B Czech 1, A Stevens 2, G Kirovski 1, M Saugspier 1, C Dorn 1, D Valletta 1, A Bosserhoff 3, P Oefner 2, C Hellerbrand 4
  • 1Department of Internal Medicine I, University of Regensburg, Regensburg
  • 2Institute of Functional Genomics, University of Regensburg, Regensburg
  • 3Institute of Pathology, University of Regensburg, Regensburg
  • 4Department of Internal Medicine I, University Regensburg, Regensburg

Methylthioadenosine phosphorylase (MTAP) the rate-limiting enzyme in the methionine and adenine salvage pathways 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 expression were reduced in the murine bile-duct ligation (BDL) model, and in addition, we detected reduced enzymatic MTAP activity. Accordingly, liquid chromatography tandem mass spectrometry revealed hepatic MTA accumulation and increased MTA serum levels in BDL-mice. In contrast, we did not observe altered MTAP expression in dietary models of non-alcoholic fatty liver disease (NAFLD). However, hepatic MTAP activity was significantly reduced in simple steatotic livers and further dropped down in mice with non-alcoholic steatohepatitis (NASH) while hepatic MTA levels increased with NAFLD-progression. Reduced MTAP expression and activity as well as MTA accumulation were confirmed in hepatic specimens of patients with chronic liver disease. In vitro stimulation of primary human hepatocytes with MTA (in concentrations found in diseased livers; up to 5 pmol/mg) we observed a dose dependant induction of proinflammatory gene expression. Further, MTA-stimulation induced activation of the transcription factor NFkappaB, profibrogenic gene expression and proliferation in hepatic stellate cells (HSC), which play a key role in hepatic fibrosis.

Conclusion: Reduced MTAP expression in chronic liver disease promotes hepatic inflammation and fibrosis via accumulation of MTA. Interestingly, in NAFLD MTAP activity is altered independent of the abundance of the protein. The identification of the underlying mechanisms of the downregulation of MTAP expression and activity, respectively, may lead to novel therapeutic strategies to prevent the progression of chronic liver disease.