Nucleoside diphosphate kinases 1 and 2 regulate a protective liver response to a high-fat diet
Domenico Iuso, I. Garcia-Saez, Yohann Couté, Yoshiki Yamaryo‐Botté, Elisabetta Boeri Erba, Annie Adrait, Nour Zeaiter, Małgorzata Tokarska-Schlattner, Zuzana Macek Jílková, Fayçal Boussouar, Sophie Barral, Luca Signor, Karine Couturier, Azadeh Hajmirza, Florent Chuffart, Ekaterina Bourova-Flin, Anne-Laure Vitte, Lisa Bargier, Denis Puthier, Thomas Decaens, Sophie Rousseaux, Cyrille Y. Botté, Uwe Schlattner, Carlo Petosa, Saadi Khochbin
Abstract
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′ 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.