Acetate supplementation modulates brain histone acetylation and decreases interleukin-1β expression in a rat model of neuroinflammation

Background: long-term acetate supplementation reduces neuroglial activation and cholinergic cell loss in a rat model of lipopolysaccharide-induced neuroinflammation. additionally,a single dose of glyceryl triacetate,used to induce acetate supplementation,increases histone h3 and h4 acetylation and inhibits histone deacetylase activity and histone deacetylase-2 expression in normal rat brain. here,we propose that the therapeutic effect of acetate in reducing neuroglial activation is due to a reversal of lipopolysaccharide-induced changes in histone acetylation and pro-inflammatory cytokine expression.methods: in this study,we examined the effect of a 28-day-dosing regimen of glyceryl triacetate,to induce acetate supplementation,on brain histone acetylation and interleukin-1β expression in a rat model of lipopolysaccharide-induced neuroinflammation. the effect was analyzed using western blot analysis,quantitative real-time polymerase chain reaction and enzymic histone deacetylase and histone acetyltransferase assays. statistical analysis was performed using one-way analysis of variance,parametric or nonparametric when appropriate,followed by tukey's or dunn's post-hoc test,respectively.results: we found that long-term acetate supplementation increased the proportion of brain histone h3 acetylated at lysine 9 (h3k9),histone h4 acetylated at lysine 8 and histone h4 acetylated at lysine 16. however,unlike a single dose of glyceryl triacetate,long-term treatment increased histone acetyltransferase activity and had no effect on histone deacetylase activity,with variable effects on brain histone deacetylase class i and ii expression. in agreement with this hypothesis,neuroinflammation reduced the proportion of brain h3k9 acetylation by 50%,which was effectively reversed with acetate supplementation. further,in rats subjected to lipopolysaccharide-induced neuroinflammation,the pro-inflammatory cytokine interleukin-1β protein and mrna levels were increased by 1.3- and 10-fold,respectively,and acetate supplementation reduced this expression to control levels.conclusion: based on these results,we conclude that dietary acetate supplementation attenuates neuroglial activation by effectively reducing pro-inflammatory cytokine expression by a mechanism that may involve a distinct site-specific pattern of histone acetylation and histone deacetylase expression in the brain. © 2012 soliman et al; licensee biomed central ltd.