bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2021‒12‒26
three papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

  1. Elife. 2021 Dec 23. pii: e60311. [Epub ahead of print]10
      Myocardial infarction (MI) is accompanied by severe energy deprivation and extensive epigenetic changes. However, how energy metabolism and chromatin modifications are interlinked during MI and heart repair has been poorly explored. Here, we examined the effect of different carbon sources that are involved in the major metabolic pathways of acetyl-CoA synthesis on myocardial infarction and found that elevation of acetyl-CoA by sodium octanoate (8C) significantly improved heart function in ischemia reperfusion (I/R) rats. Mechanistically, 8C reduced I/R injury by promoting histone acetylation which in turn activated the expression of antioxidant genes and inhibited cardiomyocyte (CM) apoptosis. Furthermore, we elucidated that 8C-promoted histone acetylation and heart repair were carried out by metabolic enzyme medium-chain acyl-CoA dehydrogenase (MCAD) and histone acetyltransferase Kat2a, suggesting that 8C dramatically improves cardiac function mainly through metabolic acetyl-CoA-mediated histone acetylation. Therefore, our study uncovers an interlinked metabolic/epigenetic network comprising 8C, acetyl-CoA, MCAD, and Kat2a to combat heart injury.
    Keywords:  cell biology; mouse
  2. J Biol Chem. 2021 Dec 17. pii: S0021-9258(21)01311-9. [Epub ahead of print] 101501
      Activated macrophages undergo metabolic reprogramming which not only supports their energetic demands but also allows for the production of specific metabolites that function as signalling molecules. Several Krebs cycle, or Krebs cycle-derived metabolites, including succinate, α-ketoglutarate and itaconate, have recently been shown to modulate macrophage function. The accumulation of 2-hydroxyglutarate (2HG) has also been well documented in transformed cells, and more recently shown to play a role in T cell and dendritic cell function. Here we have found that the abundance of both enantiomers of 2HG are increased in LPS-activated macrophages. We show that L-2HG, but not D-2HG, can promote the expression of the proinflammatory cytokine IL-1β and the adoption of an inflammatory, highly glycolytic metabolic state. These changes are likely mediated through activation of the transcription factor hypoxia inducible factor-1α (HIF-1α) by L-2HG, a known inhibitor of the HIF prolyl hydroxylases. Expression of the enzyme responsible for L-2HG degradation, L-2HG dehydrogenase (L-2HGDH), was also found to be decreased in LPS-stimulated macrophages and may therefore also contribute to L-2HG accumulation. Finally, over-expression of L-2HGDH in HEK293 TLR4/MD2/CD14 cells inhibited HIF-1α activation by LPS, whilst knockdown of L-2HGDH in macrophages boosted the induction of HIF-1α-dependent genes, as well as increasing LPS-induced HIF-1α activity. Taken together, this study therefore identifies L-2HG as a metabolite that can regulate HIF-1α in macrophages.
    Keywords:  L-2-hydroxyglutarate; glycolysis; hypoxia‐inducible factor (HIF); immunometabolism; inflammation; interleukin 1β (IL‐1β); macrophage
  3. J Cell Biochem. 2021 Dec 20.
      Acetylation of proteins seems a widespread process found in the three domains of life. Several studies have shown that besides histones, acetylation of lysine residues also occurs in non-nuclear proteins. Hence, it has been suggested that this covalent modification is a mechanism that might regulate diverse metabolic pathways by modulating enzyme activity, stability, and/or subcellular localization or interaction with other proteins. However, protein acetylation levels seem to have low correlation with modification of enzyme activity and pathway fluxes. In addition, the results obtained with mutant enzymes that presumably mimic acetylation have frequently been over-interpreted. Moreover, there is a generalized lack of rigorous enzyme kinetic analysis in parallel to acetylation level determinations. The purpose of this review is to analyze the current findings on the impact of acetylation on metabolic enzymes and its repercussion on metabolic pathways function/regulation.
    Keywords:  Krebs cycle; covalent regulation; energy metabolism; enzyme kinetics; glycolysis; modeling