Czech, Barbara and Dettmer, Katja and Valletta, Daniela and Saugspier, Michael and Koch, Andreas and Stevens, Axel P. and Thasler, Wolfgang E. and Mueller, Martina and Oefner, Peter J. and Bosserhoff, Anja-Katrin and Hellerbrand, Claus (2013) Expression and Function of Methylthioadenosine Phosphorylase in Chronic Liver Disease. PLOS ONE, 8 (12): UNSP e8070. ISSN 1932-6203,
Full text not available from this repository. (Request a copy)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. Design: 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, NF.B 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. Conclusion: MTAP mediated regulation of MTA links polyamine metabolism with NF.B activation and apoptosis in HSCs. MTAP and MTAP modulating mechanisms appear as promising prognostic markers and therapeutic targets for hepatic fibrosis.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HEPATIC STELLATE CELLS; ADENOSYL-L-METHIONINE; NF-KAPPA-B; HEPATOCELLULAR-CARCINOMA; S-ADENOSYLMETHIONINE; RAT HEPATOCYTES; OXIDATIVE STRESS; DNA METHYLATION; DOWN-REGULATION; FIBROSIS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin I |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 23 Mar 2020 09:08 |
| Last Modified: | 23 Mar 2020 09:08 |
| URI: | https://pred.uni-regensburg.de/id/eprint/15536 |
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