Role of methylthioadenosine phosphorylase (MTAP) in hepatic stellate cell activation
The activation of hepatic stellate cells (HSCs) is a key event of hepatic fibrosis, and the polyamine metabolic pathway has been implicated to affects hepatic fibrosis. 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 the role of MTAP in HSCs.
Methods and Results: Quantitative PCR and Westernblot analyses revealed increased MTAP expression during in vitro HSC activation, and immunohistochemical analysis showed a strong MTAP immunosignal in activated HSCs in cirrhotic livers. MTAP suppression by siRNA enhanced intracellular MTA levels as well as MTA levels in the supernatant of activated HSCs as assessed by liquid chromatography tandem mass spectrometry. Furthermore, MTAP suppression induced resistance against apoptosis in HSCs while overexpression of MTAP reduced MTA levels and apoptosis resistance in HSCs. Moreover, MTA stimulation of activated HSCs induced activation of NFkappaB and resistance against apoptosis. 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. Notably, we found a significant correlation between MTA-levels and the expression of collagen I in diseased human liver tissue.
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.