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.


CONCLUSIONS
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.
Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, Germany.
Witigo
W
von Schönfels
Eleonora
E
Patsenker
René
R
Fahrner
Timo
T
Itzel
Holger
H
Hinrichsen
Mario
M
Brosch
Wiebke
W
Erhart
Auste
A
Gruodyte
Bernd
B
Vollnberg
Klaus
K
Richter
Andreas
A
Landrock
Stefan
S
Schreiber
Stephan
S
Brückner
Guido
G
Beldi
Bence
B
Sipos
Thomas
T
Becker
Christoph
C
Röcken
Andreas
A
Teufel
Felix
F
Stickel
Clemens
C
Schafmayer
Jochen
J
Hampe
D000818:Animals; D001706:Biopsy; D019587:Dietary Supplements; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006873:Hydroquinones / Q000378:metabolism / Q000494:pharmacology; D008099:Liver / Q000473:pathology*; D055442:Metabolome / Q000502:physiology*; D055432:Metabolomics / Q000379:methods*; D051379:Mice; D009525:Niacin / Q000378:metabolism / Q000494:pharmacology; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control*; D018709:Statistics, Nonparametric
D006873:Hydroquinones; D009525:Niacin; C031927:hydroquinone