Serum acid sphingomyelinase is upregulated in chronic hepatitis C infection and non alcoholic fatty liver disease.
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.


CONCLUSIONS
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.
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.
Georgios
G
Grammatikos
Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University Erlangen-Nuremberg, Germany.
Christiane
C
Mühle
Pharmazentrum Frankfurt, Institut für klinische Pharmakologie, Goethe University Hospital, Frankfurt am Main, Germany.
Nerea
N
Ferreiros
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Frankfurt am Main, Germany; Goethe University Hospital, Medizinische Klinik 1, Frankfurt am Main, Germany.
Sirkka
S
Schroeter
Goethe University Hospital, Medizinische Klinik 1, Frankfurt am Main, Germany.
Dimitra
D
Bogdanou
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Frankfurt am Main, Germany.
Stephanie
S
Schwalm
Zentrallabor, Goethe University Hospital, Frankfurt am Main, Germany.
Gudrun
G
Hintereder
Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University Erlangen-Nuremberg, Germany.
Johannes
J
Kornhuber
Goethe University Hospital, Medizinische Klinik 1, Frankfurt am Main, Germany.
Stefan
S
Zeuzem
Goethe University Hospital, Medizinische Klinik 1, Frankfurt am Main, Germany.
Christoph
C
Sarrazin
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Frankfurt am Main, Germany.
Josef
J
Pfeilschifter
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D002518:Ceramides / Q000097:blood; D005234:Fatty Liver / Q000097:blood* / Q000235:genetics / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D016174:Hepacivirus; D019698:Hepatitis C, Chronic / Q000097:blood* / Q000235:genetics / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000097:blood* / Q000235:genetics; D013110:Sphingosine / Q000097:blood
D015415:Biomarkers; D002518:Ceramides; C109343:dihydroceramide; D013108:Sphingomyelin Phosphodiesterase; D013110:Sphingosine
ASM; Ceramide; HCV; NAFLD; S1P; Sphingosine