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

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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.

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Acknowledgments

We extend our sincere gratitude to Dr. Walter T. Klimecki for his valued scientific advice and contribution to the development of the human NAFLD microarray data set. We also thank Jose Munoz-Rodriguez and the Genomics Core Facility at the University of Arizona Cancer Center for the processing, archiving, and data acquisition of the microarrays. The authors also thank the National Institutes of Health (NIH)-sponsored Liver Tissue Cell Distribution System members for their help in the acquisition of human liver tissue at the University of Minnesota, Virginia Commonwealth and the University of Pittsburgh. This work was supported by the National Institutes of Health Grants, [AI083927], [HD062489], [ES006694]; the National Institute of Environmental Health Science Toxicology Training Grant [ES007091]; the Academy of Sciences of the Czech Republic with institutional support [RVO:60077344], and the Liver Tissue Cell Distribution System National Institutes of Health Contract [NO1-DK-7-0004/HHSN267200700004C].

Conflict of interest

The authors declare that there are no conflicts of interest, financial or otherwise that would influence the performance or presentation of work in this manuscript.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, The University of Arizona, 1703 East Mabel St, PO Box 210207, Tucson, AZ, 85721, USA

    April D. Lake, Richard R. Vaillancourt & Nathan J. Cherrington

  2. Biology Centre ASCR, Institute of Plant Molecular Biology, České Budějovice, Czech Republic

    Petr Novak

  3. Bristol-Myers Squibb Co, Pharmaceutical Candidate Optimization, Princeton, NJ, USA

    Petia Shipkova, Nelly Aranibar, Donald G. Robertson, Michael D. Reily & Lois D. Lehman-McKeeman

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  1. April D. Lake
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Correspondence to Nathan J. Cherrington.

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Lake, A.D., Novak, P., Shipkova, P. et al. Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease. Amino Acids 47, 603–615 (2015). https://doi.org/10.1007/s00726-014-1894-9

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  • DOI: https://doi.org/10.1007/s00726-014-1894-9

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