Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease

April D. Lake, Petr Novak, Petia Shipkova, Nelly Aranibar, Donald G. Robertson, Michael D. Reily, Lois D. Lehman-Mckeeman, Richard Vaillancourt, Nathan J Cherrington

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a globally widespread disease of increasing clinical significance. The pathological progression of the disease from simple steatosis to nonalcoholic steatohepatitis (NASH) has been well defined, however, the contribution of altered branched chain amino acid metabolomic profiles to the progression of NAFLD is not known. The three BCAAs: leucine, isoleucine and valine are known to mediate activation of several important hepatic metabolic signaling pathways ranging from insulin signaling to glucose regulation. The purpose of this study is to profile changes in hepatic BCAA metabolite levels with transcriptomic changes in the progression of human NAFLD to discover novel mechanisms of disease progression. Metabolomic and transcriptomic data sets representing the spectrum of human NAFLD (normal, steatosis, NASH fatty, and NASH not fatty livers) were utilized for this study. During the transition from steatosis to NASH, increases in the levels of leucine (127 % of normal), isoleucine (139 %), and valine (147 %) were observed. Carnitine metabolites also exhibited significantly elevated profiles in NASH fatty and NASH not fatty samples and included propionyl, hexanoyl, lauryl, acetyl and butyryl carnitine. Amino acid and BCAA metabolism gene sets were significantly enriched among downregulated genes during NASH. These cumulative alterations in BCAA metabolite and amino acid metabolism gene profiles represent adaptive physiological responses to disease-induced hepatic stress in NASH patients.

Original languageEnglish (US)
Pages (from-to)603-615
Number of pages13
JournalAmino Acids
Volume47
Issue number3
DOIs
StatePublished - 2015

Fingerprint

Branched Chain Amino Acids
Metabolism
Liver
Metabolites
Carnitine
Isoleucine
Genes
Valine
Leucine
Metabolomics
Amino Acids
Disease Progression
Non-alcoholic Fatty Liver Disease
Acetylcarnitine
Chemical activation
Fatty Liver
Insulin
Metabolic Networks and Pathways
Glucose
Down-Regulation

Keywords

  • Branched-chain amino acids
  • Metabolomics
  • Nonalcoholic fatty liver disease
  • Nonalcoholic steatohepatitis
  • Transcriptomics

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease. / Lake, April D.; Novak, Petr; Shipkova, Petia; Aranibar, Nelly; Robertson, Donald G.; Reily, Michael D.; Lehman-Mckeeman, Lois D.; Vaillancourt, Richard; Cherrington, Nathan J.

In: Amino Acids, Vol. 47, No. 3, 2015, p. 603-615.

Research output: Contribution to journalArticle

Lake, AD, Novak, P, Shipkova, P, Aranibar, N, Robertson, DG, Reily, MD, Lehman-Mckeeman, LD, Vaillancourt, R & Cherrington, NJ 2015, 'Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease', Amino Acids, vol. 47, no. 3, pp. 603-615. https://doi.org/10.1007/s00726-014-1894-9
Lake, April D. ; Novak, Petr ; Shipkova, Petia ; Aranibar, Nelly ; Robertson, Donald G. ; Reily, Michael D. ; Lehman-Mckeeman, Lois D. ; Vaillancourt, Richard ; Cherrington, Nathan J. / Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease. In: Amino Acids. 2015 ; Vol. 47, No. 3. pp. 603-615.
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AB - Nonalcoholic fatty liver disease (NAFLD) is a globally widespread disease of increasing clinical significance. The pathological progression of the disease from simple steatosis to nonalcoholic steatohepatitis (NASH) has been well defined, however, the contribution of altered branched chain amino acid metabolomic profiles to the progression of NAFLD is not known. The three BCAAs: leucine, isoleucine and valine are known to mediate activation of several important hepatic metabolic signaling pathways ranging from insulin signaling to glucose regulation. The purpose of this study is to profile changes in hepatic BCAA metabolite levels with transcriptomic changes in the progression of human NAFLD to discover novel mechanisms of disease progression. Metabolomic and transcriptomic data sets representing the spectrum of human NAFLD (normal, steatosis, NASH fatty, and NASH not fatty livers) were utilized for this study. During the transition from steatosis to NASH, increases in the levels of leucine (127 % of normal), isoleucine (139 %), and valine (147 %) were observed. Carnitine metabolites also exhibited significantly elevated profiles in NASH fatty and NASH not fatty samples and included propionyl, hexanoyl, lauryl, acetyl and butyryl carnitine. Amino acid and BCAA metabolism gene sets were significantly enriched among downregulated genes during NASH. These cumulative alterations in BCAA metabolite and amino acid metabolism gene profiles represent adaptive physiological responses to disease-induced hepatic stress in NASH patients.

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