von Schönfels, Witigo; Patsenker, Eleanora; Fahrner, René; Itzel, Timo; Hinrichsen, Holger; Brosch, Mario; Erhart, Wiebke; Gruodyte, Auste; Vollnberg, Bernd; Richter, Klaus; Landrock, Andreas; Schreiber, Stefan; Brückner, Stephan; Beldi, Guido; Sipos, Bence; Becker, Thomas; Röcken, Christoph; Teufel, Andreas; Stickel, Felix; Schafmayer, Clemens; ... (2014). Metabolomic tissue signature in human non-alcoholic fatty liver disease identifies protective candidate metabolites. Liver international, 35(1), pp. 207-214. Blackwell Munksgaard 10.1111/liv.12476
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Background
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in industrialized countries, yet its pathophysiology is incompletely understood. Small-molecule metabolite screens may offer new insights into disease mechanisms and reveal new treatment targets.
Methods
Discovery (N = 33) and replication (N = 66) of liver biopsies spanning the range from normal liver histology to non-alcoholic steatohepatitis (NASH) were ascertained ensuring rapid freezing under 30 s in patients. 252 metabolites were assessed using GC/MS. Replicated metabolites were evaluated in a murine high-fat diet model of NAFLD.
Results
In a two-stage metabolic screening, hydroquinone (HQ, pcombined = 3.0 × 10−4) and nicotinic acid (NA, pcombined = 3.9 × 10−9) were inversely correlated with histological NAFLD severity. A murine high-fat diet model of NAFLD demonstrated a protective effect of these two substances against NAFLD: Supplementation with 1% HQ reduced only liver steatosis, whereas 0.6% NA reduced both liver fat content and serum transaminase levels and induced a complex regulatory network of genes linked to NALFD pathogenesis in a global expression pathway analysis. Human nutritional intake of NA equivalent was also consistent with a protective effect of NA against NASH progression.
Conclusion
This first small-molecular screen of human liver tissue identified two replicated protective metabolites. Either the use of NA or targeting its regulatory pathways might be explored to treat or prevent human NAFLD.
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