Our observation of increased

histone acetylation in a mac

Our observation of increased

histone acetylation in a macrophage cell line after ethanol treatment is consistent with the findings of other groups that have recently demonstrated that ethanol increases histone acetylation in hepatocytes,28 hepatic stellate cells,29 and whole rat tissues.17 However, the present study is the first demonstration of ethanol modulation of gene expression in inflammatory cells by a mechanism dependent on histone acetylation. This increased acetylation could, in principle, arise through a number of routes. Ethanol metabolism, particularly at higher concentrations, produces a significant burden of reactive oxygen species (ROS)30 Mitomycin C nmr and endoplasmic reticulum (ER) stress.31 ROS can directly activate transcription factors such as nuclear factor kappaB (NF-κB)p6532 and oxidative and ER stress can favor a proinflammatory transcription factor milieu.33 NF-κBp65 will recruit HAT coactivators to proinflammatory gene promoters and increase histone acetylation. Additionally, oxidative stress is known to inhibit HDAC recruitment to actively transcribed chromatin.34 However, critically, we have shown that exposure to acetate, the principal hepatic endproduct of ethanol metabolism, can fully mimic the effects on cytokine production seen with ethanol. As cytokine potentiation can occur without this website the

ROS-generating metabolism of ethanol to acetate, then oxidative stress cannot be solely responsible for the enhanced inflammatory response to ethanol. We observed that both ethanol and its metabolite acetate could reduce HDAC activity in a cell-free system, with a similar pattern observed in cell lysates after 7 days culture. Free acetate is the endproduct of histone deacetylation, so acetate may increase histone acetylation through endproduct inhibition of HDACs. Acetate may also increase histone acetylation through increased HAT activity. This could

be through increased substrate supply (although for this acetate must be in the form of acetyl-coA) or indirectly through reduced HDAC activity. HDACs have a role in deacetylation of NF-κBp65 leading to a reduction in its ability to recruit HAT coactivators, so reduced HDAC activity can lead to increased HAT recruitment.35 Ethanol and acetate might also influence total HDAC activity by MRIP modulating the activity of SIRTs. These are class III HDACs whose activity is dependent on the presence of NAD+ and which are increasingly recognized as a vital link between energy supply, gene expression, cellular activity, and cellular aging.16 There is recent evidence that ethanol can reduce total HDAC activity.18 Metabolism of ethanol to acetate results in NAD+ depletion which will reduce SIRT and hence total HDAC activity. Free acetate will not affect NAD+, but once converted to acetyl-coA it can enter the Krebs cycle and convert NAD+ to NADH in the same way as if it had come from glycolysis or fatty acid oxidation.

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