Nucleoside Diphosphate Kinases 1 and 2 regulate a protective liver response to a high-fat diet

Iuso, D.; Garcia-Saez, I.; Coute, Y.; Yamaryo-Botte, Y.; Erba, E. B.; Adrait, A.; Zeaiter, N.; Tokarska-Schlattner, M.; Jilkova, Z. M.; Boussouar, F.; Barral, S.; Signor, L.; Couturier, K.; Hajmirza, A.; Chuffart, F.; Vitte, A.-L.; Bargier, L.; Puthier, D.; Decaens, T.; Rousseaux, S.; Botte, C. Y.; Schlattner, U.; Petosa, C.; Khochbin, S.

doi:10.1101/2023.01.15.524116

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bioRxiv · 10.1101/2023.01.15.524116

Nucleoside Diphosphate Kinases 1 and 2 regulate a protective liver response to a high-fat diet

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Abstract

De novo lipogenesis (DNL), the process whereby cells synthesize fatty acids from acetyl-coenzyme A (acetyl-CoA), is deregulated in diverse pathologies, including cancer. Here we report that DNL is negatively regulated by Nucleoside Diphosphate Kinases 1 and 2 (NME1/2), housekeeping enzymes involved in nucleotide homeostasis that were recently discovered to bind co-enzyme A (CoA). We show that NME1 additionally binds acetyl-CoA and that ligand recognition involves a unique binding mode dependent on the CoA/acetyl-CoA 3 phosphate. We report that Nme2 knockout mice fed a high-fat diet (HFD) exhibit excessive triglyceride synthesis and liver steatosis. In liver cells NME2 mediates a gene transcriptional response to HFD leading to DNL repression and activation of a protective gene expression program via targeted histone acetylation. Our findings implicate NME1/2 in the epigenetic regulation of a protective liver response to HFD and suggest a potential role in controlling acetyl-CoA usage between the competing paths of histone acetylation and DNL.

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Iuso, D., Garcia-Saez, I., Coute, Y., Yamaryo-Botte, Y., Erba, E. B., Adrait, A., Zeaiter, N., Tokarska-Schlattner, M., Jilkova, Z. M., Boussouar, F., Barral, S., Signor, L., Couturier, K., Hajmirza, A., Chuffart, F., Vitte, A.-L., Bargier, L., Puthier, D., Decaens, T., Rousseaux, S., Botte, C. Y., Schlattner, U., Petosa, C., Khochbin, S.. 2023-01-18. Nucleoside Diphosphate Kinases 1 and 2 regulate a protective liver response to a high-fat diet. https://doi.org/10.1101/2023.01.15.524116

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