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Revisiting the role of serine metabolism in hepatic lipogenesis

Nature Metabolism volume 5, pages 760–761 (2023)Cite this article

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Matters Arising to this article was published on 11 May 2023

The Original Article was published on 29 November 2021

arising from Z. Zhang et al. Nature Metabolism https://doi.org/10.1038/s42255-021-00487-4 (2021)

De novo lipogenesis (DNL) is a constitutive pathway that requires the reductive power of NADPH and cytosolic acetyl-CoA. Although elevated hepatic DNL has been implied in the pathogenesis of diverse diseases including non-alcoholic fatty liver disease (NAFLD), little is known about the source of acetyl-CoA and NADPH that fuel this process. In a recent publication in Nature Metabolism, Zhang et al.1 provided evidence that the liver uses primarily circulating acetate and lactate to make acetyl-CoA, and that cytosolic serine catabolism generates NADPH, which fuels hepatic DNL. Here, we argue that the data presented in their study cannot conclusively support their conclusion. When serine catabolism was disrupted, there was a marked decrease in DNL flux in the liver, but there was no decrease in overall tissue NADPH, serine and glutathione (GSH) levels. The authors tried to demonstrate that cytosolic serine catabolism through the SHMT1–MTHFD1–ALDH1L1 reaction sequence, in particular, acts as a primary source of NADPH for hepatic DNL in a Shmt1 whole-body knockout mouse model. They reported that Shmt1 knockout induced an 80% drop in NADPH and palmitate labelling from the tracer in the liver of these mice (as shown in Fig. 5d–f in the study1) but had no impact on overall tissue serine and NADPH concentration (as shown in Extended Data Fig. 8j in the study1). Additionally, Zhang et al. showed that the ratio of oxidized glutathione (GSSG) to reduced GSH (GSSG/GSH ratio; as shown in Extended Data Fig. 8n in the study1) did not significantly change after the knockout of Shmt1. However, when both Shmt1 and Shmt2 (isozymes of Shmt1 in mitochondria) were inhibited by a small-molecule drug, the ratio significantly increased and the liver palmitate lipogenesis flux showed a more profound decrease compared to Shmt1 knockout only (as shown in Fig. 5f in the study1), suggesting that mitochondrial serine catabolism might also contribute to NADPH production for lipogenesis. Taken together, these observations do not support the authors’ claim that cytosolic serine catabolism distinctively fuels hepatic lipogenesis.

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Acknowledgements

This work was financially supported by Knut and Alice Wallenberg Foundation (grant no. 72110).

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Authors and Affiliations

  1. Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm, Sweden

    Hong Yang, Cheng Zhang, Mathias Uhlen & Adil Mardinoglu

  2. Department of Medical Biology, Faculty of Medicine, Atatürk University, Erzurum, Turkey

    Hasan Turkez

  3. Department of Molecular and Clinical Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden

    Jan Boren

  4. Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London, UK

    Adil Mardinoglu

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Contributions

H.Y. and A.M. drafted the manuscript. C.Z., H.T., M.U. and J.B. contributed to the writing of the manuscript.

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Correspondence to Adil Mardinoglu.

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Competing interests

A.M., J.B. and M.U. are the founders and shareholders of ScandiBio Therapeutics, and they filed a patent application (US11141396B2) on the use of combined metabolic activators including serine to treat NAFLD patients. The other authors declare no competing interests.

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Nature Metabolism thanks Rotonya M. Carr and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Yang, H., Zhang, C., Turkez, H. et al. Revisiting the role of serine metabolism in hepatic lipogenesis. Nat Metab 5, 760–761 (2023). https://doi.org/10.1038/s42255-023-00792-0

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