| Experiment Id | GSE198686 | Name | Nucleoside-Diphosphate Kinase 1 and 2 are master regulators of a liver protective response to high fat diet [RNA-seq] |
| Experiment Type | RNA-Seq | Study Type | WT vs. Mutant |
| Source | GEO | Curation Date | 2025-01-06 |
| description | 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. Transcriptomic 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, RNAseq was performed in 4 replicates corresponding to 4 individual mice. |
