Serum proteomics and biomarker discovery across the spectrum of nonalcoholic fatty liver disease†‡
Lauren N. Bell
Division of Clinical Pharmacology, Indiana University, Indianapolis, IN
Division of Gastroenterology/Hepatology, Indiana University, Indianapolis, IN
Search for more papers by this authorRaj Vuppalanchi
Division of Clinical Pharmacology, Indiana University, Indianapolis, IN
Division of Gastroenterology/Hepatology, Indiana University, Indianapolis, IN
Search for more papers by this authorRomil Saxena
Division of Gastroenterology/Hepatology, Indiana University, Indianapolis, IN
Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN
Search for more papers by this authorMu Wang
Monarch LifeSciences, Indianapolis, IN
Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, IN
Search for more papers by this authorCorresponding Author
Naga Chalasani
Division of Clinical Pharmacology, Indiana University, Indianapolis, IN
Division of Gastroenterology/Hepatology, Indiana University, Indianapolis, IN
Dr. Chalasani has financial consulting agreements with several pharmaceutical companies but none pose a potential conflict.
fax: (317) 278-1949
Division of Gastroenterology/Hepatology, Indiana University School of Medicine, 1050 Wishard Boulevard, RG 4100, Indianapolis, IN 46202===Search for more papers by this authorLauren N. Bell
Division of Clinical Pharmacology, Indiana University, Indianapolis, IN
Division of Gastroenterology/Hepatology, Indiana University, Indianapolis, IN
Search for more papers by this authorRaj Vuppalanchi
Division of Clinical Pharmacology, Indiana University, Indianapolis, IN
Division of Gastroenterology/Hepatology, Indiana University, Indianapolis, IN
Search for more papers by this authorRomil Saxena
Division of Gastroenterology/Hepatology, Indiana University, Indianapolis, IN
Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN
Search for more papers by this authorMu Wang
Monarch LifeSciences, Indianapolis, IN
Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, IN
Search for more papers by this authorCorresponding Author
Naga Chalasani
Division of Clinical Pharmacology, Indiana University, Indianapolis, IN
Division of Gastroenterology/Hepatology, Indiana University, Indianapolis, IN
Dr. Chalasani has financial consulting agreements with several pharmaceutical companies but none pose a potential conflict.
fax: (317) 278-1949
Division of Gastroenterology/Hepatology, Indiana University School of Medicine, 1050 Wishard Boulevard, RG 4100, Indianapolis, IN 46202===Search for more papers by this authorPotential 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.
Dr. Chalasani has financial consulting agreements with several pharmaceutical companies but none pose a potential conflict.
fax: (317) 278-1949
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.)
Supporting Information
Additional Supporting Information may be found in the online version of this article.
Filename | Description |
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HEP_23271_sm_SupFig1.tif22.9 MB | Supporting Figure 1. Heatmap resulting from Hierarchal Clustering of the Priority 1 Proteins with a Significant Change at least 30% (q<0.05) Between Patient Groups. Proteins are clustered according to the similarities in the changes of their expression levels (mean log2 intensities) among groups of subjects (control, simple steatosis, NASH, and NASH F3/F4). Red indicates a relative increase in protein expression and green a relative decrease in protein expression, with black representing the mean-centered relative protein expression. Groups are as follows: C=obese controls, F=simple steatosis, N=NASH, R= NASH F3/F4. |
HEP_23271_sm_SupTab1.doc215 KB | Supplementary Table 1: Differentially Expressed Priority 1 Proteins with a >14% Significant Change (q<0.05) |
HEP_23271_sm_SupTab2.doc146.5 KB | Supplementary Table 2: Individual Diagnostic Accuracy of all 27 Priority 1 Proteins with a >30% Significant Change (q<0.05) |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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