Serum metabolomics reveals γ-glutamyl dipeptides as biomarkers for discrimination among different forms of liver disease

Tomoyoshi Soga, Masahiro Sugimoto, Masashi Honma, Masayo Mori, Kaori Igarashi, Kasumi Kashikura, Satsuki Ikeda, Akiyoshi Hirayama, Takehito Yamamoto, Haruhiko Yoshida, Motoyuki Otsuka, Shoji Tsuji, Yutaka Yatomi, Tadayuki Sakuragawa, Hisayoshi Watanabe, Kouei Nihei, Takafumi Saito, Sumio Kawata, Hiroshi Suzuki, Masaru TomitaMakoto Suematsu

Research output: Contribution to journalArticle

135 Citations (Scopus)

Abstract

Background & Aims: We applied a metabolome profiling approach to serum samples obtained from patients with different liver diseases, to discover noninvasive and reliable biomarkers for rapid-screening diagnosis of liver diseases. Methods: Using capillary electrophoresis and liquid chromatography mass spectrometry, we analyzed low molecular weight metabolites in a total of 248 serum samples obtained from patients with nine types of liver disease and healthy controls. Results: We found that γ-glutamyl dipeptides, which were biosynthesized through a reaction with γ-glutamylcysteine synthetase, were indicative of the production of reduced glutathione, and that measurement of their levels could distinguish among different liver diseases. Multiple logistic regression models facilitated the discrimination between specific and other liver diseases and yielded high areas under receiver-operating characteristic curves. The area under the curve values in training and independent validation data were 0.952 and 0.967 in healthy controls, 0.817 and 0.849 in drug-induced liver injury, 0.754 and 0.763 in asymptomatic hepatitis B virus infection, 0.820 and 0.762 in chronic hepatitis B, 0.972 and 0.895 in hepatitis C with persistently normal alanine transaminase, 0.917 and 0.707 in chronic hepatitis C, 0.803 and 0.993 in cirrhosis type C, and 0.762 and 0.803 in hepatocellular carcinoma, respectively. Several γ-glutamyl dipeptides also manifested potential for differentiating between nonalcoholic steatohepatitis and simple steatosis. Conclusions: γ-Glutamyl dipeptides are novel biomarkers for liver diseases, and varying levels of individual or groups of these peptides have the power to discriminate among different forms of hepatic disease.

Original languageEnglish
Pages (from-to)896-905
Number of pages10
JournalJournal of Hepatology
Volume55
Issue number4
DOIs
Publication statusPublished - 2011 Oct

Fingerprint

Metabolomics
Dipeptides
Liver Diseases
Biomarkers
Serum
Logistic Models
Glutamate-Cysteine Ligase
Chemical and Drug Induced Liver Injury
Metabolome
Chronic Hepatitis B
Capillary Electrophoresis
Chronic Hepatitis C
Virus Diseases
Hepatitis C
Alanine Transaminase
Hepatitis B virus
ROC Curve
Liquid Chromatography
Area Under Curve
Glutathione

Keywords

  • γ-Glutamyl dipeptides
  • Biomarker
  • Capillary electrophoresis mass spectrometry
  • Glutathione
  • Hepatitis C virus
  • Hepatocellular carcinoma
  • Metabolomics
  • Nonalcoholic steatohepatitis
  • Oxidative stress

ASJC Scopus subject areas

  • Hepatology

Cite this

Serum metabolomics reveals γ-glutamyl dipeptides as biomarkers for discrimination among different forms of liver disease. / Soga, Tomoyoshi; Sugimoto, Masahiro; Honma, Masashi; Mori, Masayo; Igarashi, Kaori; Kashikura, Kasumi; Ikeda, Satsuki; Hirayama, Akiyoshi; Yamamoto, Takehito; Yoshida, Haruhiko; Otsuka, Motoyuki; Tsuji, Shoji; Yatomi, Yutaka; Sakuragawa, Tadayuki; Watanabe, Hisayoshi; Nihei, Kouei; Saito, Takafumi; Kawata, Sumio; Suzuki, Hiroshi; Tomita, Masaru; Suematsu, Makoto.

In: Journal of Hepatology, Vol. 55, No. 4, 10.2011, p. 896-905.

Research output: Contribution to journalArticle

Soga, T, Sugimoto, M, Honma, M, Mori, M, Igarashi, K, Kashikura, K, Ikeda, S, Hirayama, A, Yamamoto, T, Yoshida, H, Otsuka, M, Tsuji, S, Yatomi, Y, Sakuragawa, T, Watanabe, H, Nihei, K, Saito, T, Kawata, S, Suzuki, H, Tomita, M & Suematsu, M 2011, 'Serum metabolomics reveals γ-glutamyl dipeptides as biomarkers for discrimination among different forms of liver disease', Journal of Hepatology, vol. 55, no. 4, pp. 896-905. https://doi.org/10.1016/j.jhep.2011.01.031
Soga, Tomoyoshi ; Sugimoto, Masahiro ; Honma, Masashi ; Mori, Masayo ; Igarashi, Kaori ; Kashikura, Kasumi ; Ikeda, Satsuki ; Hirayama, Akiyoshi ; Yamamoto, Takehito ; Yoshida, Haruhiko ; Otsuka, Motoyuki ; Tsuji, Shoji ; Yatomi, Yutaka ; Sakuragawa, Tadayuki ; Watanabe, Hisayoshi ; Nihei, Kouei ; Saito, Takafumi ; Kawata, Sumio ; Suzuki, Hiroshi ; Tomita, Masaru ; Suematsu, Makoto. / Serum metabolomics reveals γ-glutamyl dipeptides as biomarkers for discrimination among different forms of liver disease. In: Journal of Hepatology. 2011 ; Vol. 55, No. 4. pp. 896-905.
@article{05fadd0769a944f59dd3270a45ae6546,
title = "Serum metabolomics reveals γ-glutamyl dipeptides as biomarkers for discrimination among different forms of liver disease",
abstract = "Background & Aims: We applied a metabolome profiling approach to serum samples obtained from patients with different liver diseases, to discover noninvasive and reliable biomarkers for rapid-screening diagnosis of liver diseases. Methods: Using capillary electrophoresis and liquid chromatography mass spectrometry, we analyzed low molecular weight metabolites in a total of 248 serum samples obtained from patients with nine types of liver disease and healthy controls. Results: We found that γ-glutamyl dipeptides, which were biosynthesized through a reaction with γ-glutamylcysteine synthetase, were indicative of the production of reduced glutathione, and that measurement of their levels could distinguish among different liver diseases. Multiple logistic regression models facilitated the discrimination between specific and other liver diseases and yielded high areas under receiver-operating characteristic curves. The area under the curve values in training and independent validation data were 0.952 and 0.967 in healthy controls, 0.817 and 0.849 in drug-induced liver injury, 0.754 and 0.763 in asymptomatic hepatitis B virus infection, 0.820 and 0.762 in chronic hepatitis B, 0.972 and 0.895 in hepatitis C with persistently normal alanine transaminase, 0.917 and 0.707 in chronic hepatitis C, 0.803 and 0.993 in cirrhosis type C, and 0.762 and 0.803 in hepatocellular carcinoma, respectively. Several γ-glutamyl dipeptides also manifested potential for differentiating between nonalcoholic steatohepatitis and simple steatosis. Conclusions: γ-Glutamyl dipeptides are novel biomarkers for liver diseases, and varying levels of individual or groups of these peptides have the power to discriminate among different forms of hepatic disease.",
keywords = "γ-Glutamyl dipeptides, Biomarker, Capillary electrophoresis mass spectrometry, Glutathione, Hepatitis C virus, Hepatocellular carcinoma, Metabolomics, Nonalcoholic steatohepatitis, Oxidative stress",
author = "Tomoyoshi Soga and Masahiro Sugimoto and Masashi Honma and Masayo Mori and Kaori Igarashi and Kasumi Kashikura and Satsuki Ikeda and Akiyoshi Hirayama and Takehito Yamamoto and Haruhiko Yoshida and Motoyuki Otsuka and Shoji Tsuji and Yutaka Yatomi and Tadayuki Sakuragawa and Hisayoshi Watanabe and Kouei Nihei and Takafumi Saito and Sumio Kawata and Hiroshi Suzuki and Masaru Tomita and Makoto Suematsu",
year = "2011",
month = "10",
doi = "10.1016/j.jhep.2011.01.031",
language = "English",
volume = "55",
pages = "896--905",
journal = "Journal of Hepatology",
issn = "0168-8278",
publisher = "Elsevier",
number = "4",

}

TY - JOUR

T1 - Serum metabolomics reveals γ-glutamyl dipeptides as biomarkers for discrimination among different forms of liver disease

AU - Soga, Tomoyoshi

AU - Sugimoto, Masahiro

AU - Honma, Masashi

AU - Mori, Masayo

AU - Igarashi, Kaori

AU - Kashikura, Kasumi

AU - Ikeda, Satsuki

AU - Hirayama, Akiyoshi

AU - Yamamoto, Takehito

AU - Yoshida, Haruhiko

AU - Otsuka, Motoyuki

AU - Tsuji, Shoji

AU - Yatomi, Yutaka

AU - Sakuragawa, Tadayuki

AU - Watanabe, Hisayoshi

AU - Nihei, Kouei

AU - Saito, Takafumi

AU - Kawata, Sumio

AU - Suzuki, Hiroshi

AU - Tomita, Masaru

AU - Suematsu, Makoto

PY - 2011/10

Y1 - 2011/10

N2 - Background & Aims: We applied a metabolome profiling approach to serum samples obtained from patients with different liver diseases, to discover noninvasive and reliable biomarkers for rapid-screening diagnosis of liver diseases. Methods: Using capillary electrophoresis and liquid chromatography mass spectrometry, we analyzed low molecular weight metabolites in a total of 248 serum samples obtained from patients with nine types of liver disease and healthy controls. Results: We found that γ-glutamyl dipeptides, which were biosynthesized through a reaction with γ-glutamylcysteine synthetase, were indicative of the production of reduced glutathione, and that measurement of their levels could distinguish among different liver diseases. Multiple logistic regression models facilitated the discrimination between specific and other liver diseases and yielded high areas under receiver-operating characteristic curves. The area under the curve values in training and independent validation data were 0.952 and 0.967 in healthy controls, 0.817 and 0.849 in drug-induced liver injury, 0.754 and 0.763 in asymptomatic hepatitis B virus infection, 0.820 and 0.762 in chronic hepatitis B, 0.972 and 0.895 in hepatitis C with persistently normal alanine transaminase, 0.917 and 0.707 in chronic hepatitis C, 0.803 and 0.993 in cirrhosis type C, and 0.762 and 0.803 in hepatocellular carcinoma, respectively. Several γ-glutamyl dipeptides also manifested potential for differentiating between nonalcoholic steatohepatitis and simple steatosis. Conclusions: γ-Glutamyl dipeptides are novel biomarkers for liver diseases, and varying levels of individual or groups of these peptides have the power to discriminate among different forms of hepatic disease.

AB - Background & Aims: We applied a metabolome profiling approach to serum samples obtained from patients with different liver diseases, to discover noninvasive and reliable biomarkers for rapid-screening diagnosis of liver diseases. Methods: Using capillary electrophoresis and liquid chromatography mass spectrometry, we analyzed low molecular weight metabolites in a total of 248 serum samples obtained from patients with nine types of liver disease and healthy controls. Results: We found that γ-glutamyl dipeptides, which were biosynthesized through a reaction with γ-glutamylcysteine synthetase, were indicative of the production of reduced glutathione, and that measurement of their levels could distinguish among different liver diseases. Multiple logistic regression models facilitated the discrimination between specific and other liver diseases and yielded high areas under receiver-operating characteristic curves. The area under the curve values in training and independent validation data were 0.952 and 0.967 in healthy controls, 0.817 and 0.849 in drug-induced liver injury, 0.754 and 0.763 in asymptomatic hepatitis B virus infection, 0.820 and 0.762 in chronic hepatitis B, 0.972 and 0.895 in hepatitis C with persistently normal alanine transaminase, 0.917 and 0.707 in chronic hepatitis C, 0.803 and 0.993 in cirrhosis type C, and 0.762 and 0.803 in hepatocellular carcinoma, respectively. Several γ-glutamyl dipeptides also manifested potential for differentiating between nonalcoholic steatohepatitis and simple steatosis. Conclusions: γ-Glutamyl dipeptides are novel biomarkers for liver diseases, and varying levels of individual or groups of these peptides have the power to discriminate among different forms of hepatic disease.

KW - γ-Glutamyl dipeptides

KW - Biomarker

KW - Capillary electrophoresis mass spectrometry

KW - Glutathione

KW - Hepatitis C virus

KW - Hepatocellular carcinoma

KW - Metabolomics

KW - Nonalcoholic steatohepatitis

KW - Oxidative stress

UR - http://www.scopus.com/inward/record.url?scp=80051623540&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80051623540&partnerID=8YFLogxK

U2 - 10.1016/j.jhep.2011.01.031

DO - 10.1016/j.jhep.2011.01.031

M3 - Article

C2 - 21334394

AN - SCOPUS:80051623540

VL - 55

SP - 896

EP - 905

JO - Journal of Hepatology

JF - Journal of Hepatology

SN - 0168-8278

IS - 4

ER -