Nucleoside-Diphosphate Kinase 1 and 2 are master regulators of a liver protective response to high fat diet [ChIP-seq]

Fatty acid homeostasis is critical for normal cellular physiology and leads to severe diseases when deregulated. Here we report Nucleoside-Diphosphate Kinase 1 and 2 (NME1/2) as major cellular co-enzyme A (CoA) and acetyl-CoA binding proteins and negative regulators of de novo lipogenesis (DNL). Structural studies demonstrate that Nme1 recognizes CoA through its nucleotide moiety, which competes for binding with ADP/ATP. By using a Nme2 ko mouse model, we observe that NME2 is required for the gene transcriptional response to a high fat diet (HFD) in liver cells, leading to a repression of lipogenesis and the activation of a protective gene response. Nme2 ko mice submitted to a HFD challenge are unable to repress key lipogenic genes, resulting in an excessive triglyceride synthesis and liver steatosis. Mechanistically, the NME2-dependent down-regulation of DNL in response to HFD changes the balance for the use of acetyl-CoA between the competing paths of acetylation and DNL, thereby increasing TSS-targeted histone acetylation and gene activation. A structure-guided generation of a NME1 mutant, with intact NDK activity, but unable to bind CoA, directly demonstrates the functional impact of acetyl-CoA/CoA binding by NME1/2 in repressing DNL. Taken together, these findings highlight a yet unknow protective liver response to HFD, regulated by multi-ligand binding proteins which act as direct sensors for the cellular levels of NDP/NTP and CoA/acetyl-CoA. Overall design: ChIPseq analysis was performed in mouse liver samples obtained from 4 conditions, corresponding to two genotypes, Nme2 WT (nme2wt) and KO (nme2ko), and two experimental diets, normal diet (normal) and high fat diet (hghfat). For each condition, chromatin immunoprecipitation was performed twice in the respective livers of two independent mice using anti-H3K9ac antibody of MNase digested chromatin and both the immune-precipitated (chip) and input (inpt) materials were sequenced.