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

doi:10.1126/sciadv.adh0140

Molecular BiologyScience AdvancesSep 6, 2023

Peer-reviewed journal article

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

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

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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