39 2 Macrophage Metabolic Reprogramming in Diabetes In addition to being a metabolic intermediate, acetyl-CoA is also a substrate used by lysine acetyl transferases to reversibly transfer an acetyl group to the ε-amino group of lysine residues in target proteins. Therefore, altered levels of acetyl-CoA resulting from macrophage metabolic reprogramming will result in different levels of lysine acetylation (79). Acetylation neutralizes the positive charge on lysine, altering the way the acetylated protein interacts with surrounding proteins and other molecules, most notably histones (80). This highlights an interesting and yet still not widely studied consequence of changes in macrophage metabolism: the effect this can have on protein acetylation and consequently on gene expression. Reversible protein acetylation regulates a number of important cellular processes including gene expression via acetylation of histones. In fact, acetylation is one of the most frequent reversible posttranslational modifications histone proteins are subjected to. Other posttranslational modifications include methylation, phosphorylation, and ubiquitylation, which all regulate gene expression by influencing the folding of chromatin. Chromatin is a complex of DNA wrapped around an octamer of histone proteins, one H3/H4 tetramer, and two H2A/ H2B dimers, forming nucleosomes (81). During activation of gene transcription, the chromatin conformation changes from tightly packed to relaxed allowing DNA-binding proteins to interact with the DNA. Histone acetylation favors gene transcription because interactions of positively-charged amino groups in histones (belonging to lysine residues) with negatively charged phosphate groups in DNA will decrease due to the removal of positive charges on histones upon acetylation. Interestingly, protein acetylation also regulates the activity of enzymes involved in cellular energy metabolism such as hexokinase, pyruvate kinase isozymes M2, and pyruvate dehydrogenase (79). Protein acetylation in obesity and DMTII, immunomodulatory epigenetics as new therapies Due to the changes of intracellular acetyl-CoA concentrations in obesity and DMTII, an effect on protein acetylation and therefore posttranslational protein modifications (i.e. epigenetic modifications) seems probable. Indeed, a link between epigenetic changes and DMTII-related meta- inflammation has been reported in a variety of studies, suggesting that metabolic changes induced by obesity/DMTII can lead to epigenetic changes, which then result in transcription of pro-inflammatory genes (82,83). In particular, changes in the levels of lysine deacetylases (KDACs), enzymes responsible for the deacetylation of lysine residues in proteins, have been reported
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