Georgios Grammatikos1, Christiane Mühle2, Nerea Ferreiros3, Sirkka Schroeter4, Dimitra Bogdanou5, Stephanie Schwalm6, Gudrun Hintereder7, Johannes Kornhuber2, Stefan Zeuzem5, Christoph Sarrazin5, Josef Pfeilschifter6. 1. Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Frankfurt am Main, Germany; Goethe University Hospital, Medizinische Klinik 1, Frankfurt am Main, Germany. Electronic address: Georgios.Grammatikos@kgu.de. 2. Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University Erlangen-Nuremberg, Germany. 3. Pharmazentrum Frankfurt, Institut für klinische Pharmakologie, Goethe University Hospital, Frankfurt am Main, Germany. 4. Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Frankfurt am Main, Germany; Goethe University Hospital, Medizinische Klinik 1, Frankfurt am Main, Germany. 5. Goethe University Hospital, Medizinische Klinik 1, Frankfurt am Main, Germany. 6. Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Frankfurt am Main, Germany. 7. Zentrallabor, Goethe University Hospital, Frankfurt am Main, Germany.
Abstract
UNLABELLED: Sphingolipids constitute bioactive molecules with functional implications in homeostasis and pathogenesis of various diseases. However, the role of sphingolipids as possible disease biomarkers in chronic liver disease remains largely unexplored. In the present study we used mass spectrometry and spectrofluorometry methods in order to quantify various sphingolipid metabolites and also assess the activity of an important corresponding regulating enzyme in the serum of 72 healthy volunteers as compared to 69 patients with non-alcoholic fatty liver disease and 69 patients with chronic hepatitis C virus infection. Our results reveal a significant upregulation of acid sphingomyelinase in the serum of patients with chronic liver disease as compared to healthy individuals (p<0.001). Especially in chronic hepatitis C infection acid sphingomyelinase activity correlated significantly with markers of hepatic injury (r=0.312, p=0.009) and showed a high discriminative power. Accumulation of various (dihydro-) ceramide species was identified in the serum of patients with non-alcoholic fatty liver disease (p<0.001) and correlated significantly to cholesterol (r=0.448, p<0.001) but showed a significant accumulation in patients with normal cholesterol values as well (p<0.001). Sphingosine, a further bioactive metabolite, was also upregulated in chronic liver disease (p<0.001). However, no significant correlation to markers of hepatic injury was identified. CONCLUSION: Chronic hepatitis C virus infection and non-alcoholic fatty liver disease induce a significant upregulation of serum acid sphingomyelinase which appears as a novel biomarker in chronic hepatopathies. Further studies are required to elucidate the potential of the sphingolipid signaling pathway as putative therapeutic target in chronic liver disease.
UNLABELLED: Sphingolipids constitute bioactive molecules with functional implications in homeostasis and pathogenesis of various diseases. However, the role of sphingolipids as possible disease biomarkers in chronic liver disease remains largely unexplored. In the present study we used mass spectrometry and spectrofluorometry methods in order to quantify various sphingolipid metabolites and also assess the activity of an important corresponding regulating enzyme in the serum of 72 healthy volunteers as compared to 69 patients with non-alcoholic fatty liver disease and 69 patients with chronic hepatitis C virus infection. Our results reveal a significant upregulation of acid sphingomyelinase in the serum of patients with chronic liver disease as compared to healthy individuals (p<0.001). Especially in chronic hepatitis C infectionacid sphingomyelinase activity correlated significantly with markers of hepatic injury (r=0.312, p=0.009) and showed a high discriminative power. Accumulation of various (dihydro-) ceramide species was identified in the serum of patients with non-alcoholic fatty liver disease (p<0.001) and correlated significantly to cholesterol (r=0.448, p<0.001) but showed a significant accumulation in patients with normal cholesterol values as well (p<0.001). Sphingosine, a further bioactive metabolite, was also upregulated in chronic liver disease (p<0.001). However, no significant correlation to markers of hepatic injury was identified. CONCLUSION:Chronic hepatitis C virus infection and non-alcoholic fatty liver disease induce a significant upregulation of serum acid sphingomyelinase which appears as a novel biomarker in chronic hepatopathies. Further studies are required to elucidate the potential of the sphingolipid signaling pathway as putative therapeutic target in chronic liver disease.
Authors: Susanna Naggie; Sam Lusk; J Will Thompson; Meredith Mock; Cynthia Moylan; Joseph E Lucas; Laura Dubois; Lisa St John-Williams; M Arthur Moseley; Keyur Patel Journal: J Infect Dis Date: 2020-11-13 Impact factor: 5.226
Authors: Ruth R Magaye; Feby Savira; Yue Hua; Darren J Kelly; Christopher Reid; Bernard Flynn; Danny Liew; Bing H Wang Journal: Cell Mol Life Sci Date: 2018-12-06 Impact factor: 9.261
Authors: Georgios Grammatikos; Nerea Ferreiròs; Oliver Waidmann; Dimitra Bon; Sirkka Schroeter; Alexander Koch; Eva Herrmann; Stefan Zeuzem; Bernd Kronenberger; Josef Pfeilschifter Journal: PLoS One Date: 2015-09-18 Impact factor: 3.240
Authors: Nadine Beckmann; Deepa Sharma; Erich Gulbins; Katrin Anne Becker; Bärbel Edelmann Journal: Front Physiol Date: 2014-09-02 Impact factor: 4.566
Authors: Georgios Grammatikos; Niklas Schoell; Nerea Ferreirós; Dimitra Bon; Eva Herrmann; Harald Farnik; Verena Köberle; Albrecht Piiper; Stefan Zeuzem; Bernd Kronenberger; Oliver Waidmann; Josef Pfeilschifter Journal: Oncotarget Date: 2016-04-05