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Application of Mass Spectrometry-Based Metabolomics in Identification of Early Noninvasive Biomarkers of Alcohol-Induced Liver Disease Using Mouse Model

  • Soumen K. Manna
  • Matthew D. Thompson
  • Frank J. Gonzalez
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 815)

Abstract

A rapid, non-invasive urine test for early stage alcohol-induced liver disease (ALD) would permit risk stratification and treatment of high-risk individuals before ALD leads to irreversible liver damage and death. Urinary metabolomic studies were carried out to identify ALD-associated metabolic biomarkers using Ppara-null mouse model that is susceptible to ALD development on chronic alcohol consumption. Two successive studies were conducted to evaluate the applicability of mass spectrometry-based metabolomics in identification of ALD-specific signatures and to examine the robustness of these biomarkers against genetic background. Principal components analysis of ultraperformance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS)-generated urinary metabolic fingerprints showed that alcohol-treated wild-type and Ppara-null mice could be distinguished from control animals. It also showed that a combined endogenous biomarker panel helps to identify subjects with ALD as well as those at risk of developing ALD even without any information on alcohol intake or genetics. Quantitative analysis showed that increased excretion of indole-3-lactic acid and phenyllactic acid was a genetic background-independent signature exclusively associated with ALD pathogenesis in Ppara-null mice that showed liver pathologies similar to those observed in early stages of human ALD. These findings demonstrated that mass spectrometry-based metabolomic analysis could help in the identification of ALD-specific signatures, and that metabolites such as indole-3-lactic acid and phenyllactic acid, may serve as robust noninvasive biomarkers for early stages of ALD.

Keywords

Alcohol-induced liver disease PPARα Ppara-null mouse Steatosis Metabolomics UPLC-ESI-QTOFMS Multivariate data analysis Biomarker Genetic background Indole-3-lactic acid Phenyllactic acid 

Abbreviations

ALD

Alcohol-induced liver disease

ALT

Alanine aminotransferase

ANOVA

Analysis of variance

AST

Aspartate aminotransferase

ESI+

Electrospray ionization in positive mode

ESI−

Electrospray ionization in negative mode

MRM

Multiple reaction monitoring

NAD+

Oxidized nicotinamide adenine dinucleotide

NADH

Reduced nicotinamide adenine dinucleotide

OPLS

Orthogonal projection to latent structures

PCA

Principal components analysis

Ppara-null

Peroxisome proliferator-activated receptor alpha knockout mouse model

PPARα

Peroxisome proliferator-activated receptor alpha

UPLC-ESI-QTOF-MS

Ultraperformance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry

Notes

Acknowledgements

This work was supported by the National Cancer Institute Intramural Research Program, the National Institute of Environmental Health Sciences grant (U01ES016013).

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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Soumen K. Manna
    • 1
  • Matthew D. Thompson
    • 1
  • Frank J. Gonzalez
    • 1
  1. 1.Laboratory of Metabolism, Center for Cancer ResearchNational Cancer InstituteBethesdaUSA

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