Metabolomic tissue signature in human non-alcoholic fatty liver disease identifies protective candidate metabolites.

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, p_combined = 3.0 × 10⁻⁴) and nicotinic acid ( NA, p_combined = 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. [ABSTRACT FROM AUTHOR]