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

authors

  • 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

document type

ART

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 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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