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

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Biological Basis of Alcohol-Induced Cancer

Part of the book series: Advances in Experimental Medicine and Biology ((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.

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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

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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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Authors and Affiliations

  1. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Building 37, Room 3106, Bethesda, MD, 20892, USA

    Soumen K. Manna, Matthew D. Thompson & Frank J. Gonzalez

Authors
  1. Soumen K. Manna
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  2. Matthew D. Thompson
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  3. Frank J. Gonzalez
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Corresponding author

Correspondence to Frank J. Gonzalez .

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Editors and Affiliations

  1. Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut, USA

    Vasilis Vasiliou

  2. Distilled Spirits Council of the United States, Washington, District of Columbia, USA

    Samir Zakhari

  3. Centre of Alcohol Research, University of Heidelberg, Germany and Salem Medical Centre, Heidelberg, Germany

    Helmut K. Seitz

  4. Department of Pathology, Anatomy, & Cell, Thomas Jefferson University, Philadelphia, Pennsylvania, USA

    Jan B. Hoek

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Manna, S.K., Thompson, M.D., Gonzalez, F.J. (2015). Application of Mass Spectrometry-Based Metabolomics in Identification of Early Noninvasive Biomarkers of Alcohol-Induced Liver Disease Using Mouse Model. In: Vasiliou, V., Zakhari, S., Seitz, H., Hoek, J. (eds) Biological Basis of Alcohol-Induced Cancer. Advances in Experimental Medicine and Biology, vol 815. Springer, Cham. https://doi.org/10.1007/978-3-319-09614-8_13

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