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Nucleoside diphosphate kinases 1 and 2 regulate a protective liver response to a high-fat diet

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Iuso, Domenico | Garcia-Saez, Isabel | Couté, Yohann | Yamaryo-Botté, Yoshiki | Boeri Erba, Elisabetta | Adrait, Annie | Zeaiter, Nour | Tokarska-Schlattner, Malgorzata | Jilkova, Zuzana Macek | Boussouar, Fayçal | Barral, Sophie | Signor, Luca | Couturier, Karine | Hajmirza, Azadeh | Chuffart, Florent | Bourova-Flin, Ekaterina | Vitte, Anne-Laure | Bargier, Lisa | Puthier, Denis | Decaens, Thomas | Rousseaux, Sophie | Botté, Cyrille | Schlattner, Uwe | Petosa, Carlo | Khochbin, Saadi

Edité par CCSD ; American Association for the Advancement of Science (AAAS) -

International audience. The synthesis of fatty acids from acetyl-coenzyme A (AcCoA) is deregulated in diverse pathologies, including cancer. Here, we report that fatty acid accumulation is negatively regulated by nucleoside diphosphate kinases 1 and 2 (NME1/2), housekeeping enzymes involved in nucleotide homeostasis that were recently found to bind CoA. We show that NME1 additionally binds AcCoA and that ligand recognition involves a unique binding mode dependent on the CoA/AcCoA 3 0 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 the repression of fatty acid accumulation 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 AcCoA usage between the competing paths of histone acetylation and fatty acid synthesis.

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