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

Domenico Iuso1, Isabel Garcia-Saez2, Yohann Couté3

  • 1Univ. Grenoble Alpes, CNRS UMR 5309, INSERM U1209, Institute for Advanced Biosciences, La Tronche 38706, France.

Science Advances
|September 6, 2023
PubMed

Insights

Nucleoside diphosphate kinases 1 and 2 (NME1/2) regulate fatty acid synthesis. NME1/2 enzymes control acetyl-CoA usage, impacting liver steatosis and epigenetic histone acetylation in response to high-fat diets.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Epigenetics

Background:

  • Fatty acid synthesis from acetyl-CoA (AcCoA) is dysregulated in diseases like cancer.
  • Nucleoside diphosphate kinases 1 and 2 (NME1/2) are involved in nucleotide homeostasis and bind CoA.
  • Recent findings suggest NME1/2's role beyond nucleotide metabolism.

Purpose of the Study:

  • To investigate the role of NME1/2 in regulating fatty acid accumulation.
  • To elucidate the mechanism by which NME1/2 controls AcCoA usage.
  • To explore the involvement of NME1/2 in the liver's response to high-fat diets (HFD).

Main Methods:

  • Biochemical assays to determine AcCoA binding by NME1.
  • Analysis of Nme2 knockout mice fed a HFD.
  • Gene expression and histone acetylation analysis in liver cells.

Main Results:

  • NME1 binds AcCoA via a unique mode involving the CoA/AcCoA 3' phosphate.
  • Nme2 knockout mice on HFD show increased triglyceride synthesis and liver steatosis.
  • NME2 mediates transcriptional repression of fatty acid accumulation and activates protective gene expression via histone acetylation in response to HFD.

Conclusions:

  • NME1/2 enzymes are key regulators of fatty acid synthesis and accumulation.
  • NME1/2 play a critical role in the epigenetic regulation of the liver's protective response to HFD.
  • NME1/2 influence AcCoA partitioning between fatty acid synthesis and histone acetylation.

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