Serum proteomics and biomarker discovery across the spectrum of nonalcoholic fatty liver disease

Authors

  • Lauren N. Bell,

    1. Division of Clinical Pharmacology, Indiana University, Indianapolis, IN
    2. Division of Gastroenterology/Hepatology, Indiana University, Indianapolis, IN
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  • Janice L. Theodorakis,

    1. Monarch LifeSciences, Indianapolis, IN
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  • Raj Vuppalanchi,

    1. Division of Clinical Pharmacology, Indiana University, Indianapolis, IN
    2. Division of Gastroenterology/Hepatology, Indiana University, Indianapolis, IN
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  • Romil Saxena,

    1. Division of Gastroenterology/Hepatology, Indiana University, Indianapolis, IN
    2. Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN
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  • Kerry G. Bemis,

    1. Monarch LifeSciences, Indianapolis, IN
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  • Mu Wang,

    1. Monarch LifeSciences, Indianapolis, IN
    2. Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, IN
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  • Naga Chalasani

    Corresponding author
    1. Division of Clinical Pharmacology, Indiana University, Indianapolis, IN
    2. Division of Gastroenterology/Hepatology, Indiana University, Indianapolis, IN
    • Division of Gastroenterology/Hepatology, Indiana University School of Medicine, 1050 Wishard Boulevard, RG 4100, Indianapolis, IN 46202
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    • Dr. Chalasani has financial consulting agreements with several pharmaceutical companies but none pose a potential conflict.

    • fax: (317) 278-1949


  • Potential conflict of interest: Dr. Chalsani is a consultant for Advanced Life Sciences, Metabasis, Atherogenics, KaroBio, Lilly Pharma, Salix, Debiovision, Johnson and Johnson, Pfizer, Amylin, Axcan, Gilead, and Monarch LifeSciences.

  • Monarch LifeSciences is a proteomic service organization that represents an academic-government-private collaboration.

Abstract

Nonalcoholic fatty liver disease (NAFLD), ranging from relatively benign simple steatosis to progressive nonalcoholic steatohepatitis (NASH) and fibrosis, is an increasingly common chronic liver disease. Liver biopsy is currently the only reliable tool for staging the subtypes of NAFLD; therefore, noninvasive serum biomarkers for evaluation of liver disease and fibrosis are urgently needed. We performed this study to describe changes in the serum proteome and identify biomarker candidates in serum samples from 69 patients with varying stages of NAFLD (simple steatosis, NASH, and NASH with advanced bridging [F3/F4] fibrosis) and 16 obese controls. Using a label-free mass spectrometry-based approach we identified over 1,700 serum proteins with a peptide identification (ID) confidence level of >75%, 605 of which changed significantly between any two patient groups (false discovery rate <5%). Importantly, expression levels of 55 and 15 proteins changed significantly between the simple steatosis and NASH F3/F4 group and the NASH and NASH F3/F4 group, respectively. Classification of proteins with significant changes showed involvement in immune system regulation and inflammation, coagulation, cellular and extracellular matrix structure and function, and roles as carrier proteins in the blood. Further, many of these proteins are synthesized exclusively by the liver and could potentially serve as diagnostic biomarkers for identifying and staging NAFLD. Conclusion: This proteomic analysis reveals important information regarding the pathogenesis/progression of NAFLD and NASH and demonstrates key changes in serum protein expression levels between control subjects and patients with different stages of fatty liver. Future validation of these potential biomarkers is needed such that these proteins may be used in place of liver biopsy to facilitate diagnosis and treatment of patients with NAFLD. (HEPATOLOGY 2009.)

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