Dataset Information

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

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.

SUBMITTER: Iuso D

PROVIDER: S-EPMC10482350 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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

Iuso Domenico D Garcia-Saez Isabel I Couté Yohann Y Yamaryo-Botté Yoshiki Y Boeri Erba Elisabetta E Adrait Annie A Zeaiter Nour N Tokarska-Schlattner Malgorzata M Jilkova Zuzana Macek ZM Boussouar Fayçal F Barral Sophie S Signor Luca L Couturier Karine K Hajmirza Azadeh A Chuffart Florent F Bourova-Flin Ekaterina E Vitte Anne-Laure AL Bargier Lisa L Puthier Denis D Decaens Thomas T Rousseaux Sophie S Botté Cyrille C Schlattner Uwe U Petosa Carlo C Khochbin Saadi S

Science advances 20230906 36

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 <i>Nme2</i ...[more]

PMID: 37672589

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Project description:This dataset contains proteomic data from mice with high or low weight gain in response to a high fat diet. Both host and microbial proteins are present. In the supplemental, there are also tables and supplementary files that can be used for replicating the bioinformatic analysis. Abstract: Consumption of refined high-fat, low-fiber diets promotes development of obesity and its associated consequences. While genetics play an important role in dictating susceptibility to such obesogenic diets, mice with nearly uniform genetics exhibit marked heterogeneity in their extent of obesity in response to such diets. This suggests non-genetic determinants play a role in diet-induced obesity. Hence, we sought to identify parameters that predict, and/or correlate with, development of obesity in response to an obesogenic diet. We assayed behavior, metabolic parameters, inflammatory markers/cytokines, microbiota composition, and the fecal metaproteome, in a cohort of mice (n=50) prior to, and the 8 weeks following, administration of an obesogenic high-fat low-fiber diet. Neither behavioral testing nor quantitation of inflammatory markers broadly predicted severity of diet-induced obesity. Although, the small subset of mice that exhibited basal elevations in serum IL-6 (n=5) were among the more obese mice in the cohort. While fecal microbiota composition changed markedly in response to the obesogenic diet, it lacked the ability to predict which mice were relative prone or resistant to obesity. In contrast, fecal metaproteome analysis revealed functional and taxonomic differences among the proteins associated with proneness to obesity. Targeted interrogation of microbiota composition data successfully validated the taxonomic differences seen in the metaproteome. While future work will be needed to determine the breadth of applicability of these associations to other cohorts of animals and humans, this study nonetheless highlights the potential power of gut microbial proteins to predict and perhaps impact development of obesity.

Dataset Information

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

Publications

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

Similar Datasets

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