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Reply to: revisiting the role of serine metabolism in hepatic lipogenesis

Nature Metabolism volume 5, pages 762–764 (2023)Cite this article

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The Original Article was published on 11 May 2023

replying to Yang et al. Nature Metabolism https://doi.org/10.1038/s42255-023-00792-0 (2023)

Fat synthesis is a critical metabolic activity of liver and driven by two main substrates: acetyl-CoA and NADPH. Understanding the sources of these substrates is accordingly of major physiological importance. We recently reported that serine catabolism contributes to production of liver NADPH and supports de novo lipogenesis (DNL). The pathway’s activity in vivo was directly demonstrated using 2H tracing, both into NADPH’s redox active hydrogen and newly synthesized fatty acids. Moreover, through mouse genetics, we showed that the tracing signature depended on the cytosolic serine catabolic enzyme SHMT1. This work was, to our knowledge, the first to demonstrate a physiological role for cytosolic serine catabolism and downstream folate-dependent NADPH production.

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Fig. 1: De novo lipogenesis flux in hepatic G6PD-knockout model (control = G6PDfl/fl; hepatic ∆G6PD = Alb-Cre+ G6PDfl/fl).

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Raw data/Source data are provided with this paper.

Code availability

El-MAVEN v.12 and natural abundance correction software AccuCor are available online on GitHub (https://github.com/ElucidataInc/ElMaven/ and https://github.com/XiaoyangSu/AccuCor/).

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Authors and Affiliations

  1. Department of Chemistry, Princeton University, Princeton, NJ, USA

    Zhaoyue Zhang & Joshua D. Rabinowitz

  2. Laboratory of Molecular Genetics, The Rockefeller University, New York, NY, USA

    Zhaoyue Zhang

  3. Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA

    Tara TeSlaa & Joshua D. Rabinowitz

  4. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    Tara TeSlaa

  5. Ludwig Institute for Cancer Research, Princeton Branch, Princeton, NJ, USA

    Joshua D. Rabinowitz

Authors
  1. Zhaoyue Zhang
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  2. Tara TeSlaa
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  3. Joshua D. Rabinowitz
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Contributions

Z.Z., T.T. and J.R. wrote the manuscript. This work was funded by the Allen Foundation and by Ludwig Cancer Research.

Corresponding author

Correspondence to Joshua D. Rabinowitz.

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Competing interests

J.R. is a consultant and received research funding from Pfizer and is an adviser and stock owner in Colorado Research Partners, L.E.A.F. Pharmaceuticals, Rafael Pharmaceuticals, Barer Institute and its subsidiaries, Serien Therapeutics, Empress Therapeutics, and Agios Pharmaceuticals. J.R. is co-inventor of SHIN2 and related SHMT inhibitors, which have been patented by Princeton University. The remaining authors declare no competing interests.

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Nature Metabolism thanks the anonymous reviewers for their contribution to the peer review of this work.

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Zhang, Z., TeSlaa, T. & Rabinowitz, J.D. Reply to: revisiting the role of serine metabolism in hepatic lipogenesis. Nat Metab 5, 762–764 (2023). https://doi.org/10.1038/s42255-023-00793-z

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