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

Domenico Iuso (1) , Isabel Garcia-Saez (2) , Yohann Couté (3) , Yoshiki Yamaryo-Botté (1) , Elisabetta Boeri Erba (2) , Annie Adrait (3) , Nour Zeaiter (4) , Malgorzata Tokarska-Schlattner (4) , Zuzana Macek Jilkova (1, 5) , Fayçal Boussouar (1) , Sophie Barral (1, 4) , Luca Signor (2) , Karine Couturier (4) , Azadeh Hajmirza (1) , Florent Chuffart (1) , Ekaterina Bourova-Flin (1) , Anne-Laure Vitte (1) , Lisa Bargier (6, 7) , Denis Puthier (6, 7) , Thomas Decaens (1, 5) , Sophie Rousseaux (1) , Cyrille Botté (1) , Uwe Schlattner (4) , Carlo Petosa (2) , Saadi Khochbin (1)

1 IAB - Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble)
2 IBS - UMR 5075 - Institut de biologie structurale
3 UMR BioSanté - BioSanté
4 LBFA - Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée
5 Pôle DigiDune
6 TAGC - Theories and Approaches of Genomic Complexity
7 TGML - Transcriptomics and Genomics of Marseille-Luminy

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.

Domaines: Sciences du Vivant [q-bio]

Domenico Iuso, Isabel Garcia-Saez, Yohann Couté, Yoshiki Yamaryo-Botté, Elisabetta Boeri Erba, et al.. Nucleoside diphosphate kinases 1 and 2 regulate a protective liver response to a high-fat diet. Science Advances , 2023, 9 (36), pp.eadh0140. ⟨10.1126/sciadv.adh0140⟩. ⟨hal-04216158⟩