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Direct assessment of hepatic mitochondrial oxidative and anaplerotic fluxes in humans using dynamic 13C magnetic resonance spectroscopy

Nature Medicine volume 20, pages 98102 (2014) | Download Citation

Abstract

Despite the central role of the liver in the regulation of glucose and lipid metabolism, there are currently no methods to directly assess hepatic oxidative metabolism in humans in vivo. By using a new 13C-labeling strategy in combination with 13C magnetic resonance spectroscopy, we show that rates of mitochondrial oxidation and anaplerosis in human liver can be directly determined noninvasively. Using this approach, we found the mean rates of hepatic tricarboxylic acid (TCA) cycle flux (VTCA) and anaplerotic flux (VANA) to be 0.43 ± 0.04 μmol g−1 min−1 and 0.60 ± 0.11 μmol g−1 min−1, respectively, in twelve healthy, lean individuals. We also found the VANA/VTCA ratio to be 1.39 ± 0.22, which is severalfold lower than recently published estimates using an indirect approach. This method will be useful for understanding the pathogenesis of nonalcoholic fatty liver disease and type 2 diabetes, as well as for assessing the effectiveness of new therapies targeting these pathways in humans.

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Acknowledgements

We thank A. Impellizeri, Y. Kosover, I. Smolgovsky, M. Smolgovsky, G. Solomon, C. Parmelee and the staff of the Yale Center for Clinical Investigation Hospital Research Unit for their technical support and the volunteers for their participation in these studies. We also acknowledge the contributions of G. Mason, who assisted in the implementation and interpretation of the metabolic modeling of the rat [1-13C]acetate infusion data. This publication was supported by grants from the US Public Health Service (R24 DK-085638, R01 AG-23686, R01 DK-49230, P30 DK-45735 and UL1 RR-024139), a Distinguished Clinical Investigator Award from the American Diabetes Association (K.F.P.) and an investigator-initiated grant from Pfizer (K.F.P.). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the US National Center for Research Resources or National Institutes of Health.

Author information

Author notes

    • Douglas E Befroy
    •  & Rachel J Perry

    These authors contributed equally to this work.

Affiliations

  1. Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut, USA.

    • Douglas E Befroy
    •  & Douglas L Rothman
  2. Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.

    • Douglas E Befroy
    • , Rachel J Perry
    • , Gary W Cline
    • , Kitt Falk Petersen
    •  & Gerald I Shulman
  3. Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA.

    • Rachel J Perry
    •  & Gerald I Shulman
  4. Department of Biomedical Engineering, Yale University School of Medicine, New Haven, Connecticut, USA.

    • Nimit Jain
    •  & Douglas L Rothman
  5. Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.

    • Sylvie Dufour
    •  & Gerald I Shulman
  6. Pfizer Pharmaceuticals, Groton, Connecticut, USA.

    • Jeff K Trimmer
    •  & Julia Brosnan
  7. Novo Nordisk Foundation Center for Basic Metabolic Research, Copenhagen, Denmark.

    • Kitt Falk Petersen
    •  & Gerald I Shulman

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Contributions

D.E.B., R.J.P., J.T., J.B., K.F.P., D.L.R. and G.I.S. designed the experimental protocols. D.E.B., R.J.P., S.D., G.W.C. and K.F.P. performed the studies. D.E.B., N.J., R.J.P., S.D., G.W.C. and D.L.R. analyzed the data. D.E.B., R.J.P., K.F.P., D.L.R. and G.I.S. contributed to the writing of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Gerald I Shulman.

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    Supplementary Text and Figures

    Supplementary Tables 1 and 2, Supplementary Figures 1–3 and Supplementary Methods

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DOI

https://doi.org/10.1038/nm.3415

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