Metabolomic tissue signature in human non-alcoholic fatty liver disease identifies protective candidate metabolites.
Liver Int
; 35(1): 207-14, 2015 Jan.
Article
em En
| MEDLINE
| ID: mdl-24484068
ABSTRACT
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.
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Base de dados:
MEDLINE
Assunto principal:
Metaboloma
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Metabolômica
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Hepatopatia Gordurosa não Alcoólica
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Fígado
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article