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

Abstract

BackgroundLong-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.MethodsIn 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.ResultsWe 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.ConclusionBased 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.

Cationic lipid-based nanoparticles mediate functional delivery of acetate to tumor cells in vivo leading to significant anticancer effects

“…22,25 The anti-proliferative effects of SCFA have been linked to the enteric generation of acetate in several models of malignancy, 1,4 with additional studies further linking these changes to SCFA-induced alterations in the activities of HDAC enzymes. 5,10 In line with these data, we demonstrated that LITA-CAN administration leads to a significant reduction in the tumor growth and a concomitant reduction in the selected HDAC expression. The decreased expression of HDAC SirT1 is of particular note given its established role as an inhibitor of apoptosis and promoter for tumorigenesis.…”

“…1,4 HDACs are important epigenetic markers that play a key role in modulating the expression of genes involved in cellular proliferation, apoptosis and differentiation. 5,6 As such, they represent an integrated target for cancer therapy, with the ineffectual metabolism of SCFA in cancer cells hypothesized to lead to an accumulation of acetyl-CoA in the nucleus, where it functions as an HDAC inhibitor. 7 Previous studies have attempted to target and disrupt the altered cellular metabolism in colonic cancer cells via supplementation with SCFA.…”

Acetate supplementation modulates brain adenosine metabolizing enzymes and adenosine A2Areceptor levels in rats subjected to neuroinflammation

“…We found that at 14 days, LPS-induced neuroinflammation caused a significant increase in A 2A receptor levels compared to controls (Figure 1), in line with our previous findings that show an increase in IL-1β expression [20], which is known to increase A 2A receptor levels [57]. Fourteen-day prophylactic acetate supplementation prevented this LPS-induced increase (Figure 1) in A 2A receptors, which is in agreement with results demonstrating that GTA attenuates LPS-induced pro-inflammatory cytokine release [20]. Since blockade of A 2A receptor prevents IL-1β induced exacerbation of neuronal toxicity [58], acetate supplementation has a combined effect of reducing IL-1β levels and A 2A receptors that can offer robust neuroprotection by attenuating neuroinflammation.…”

Acetate supplementation reduces microglia activation and brain interleukin-1β levels in a rat model of Lyme neuroborreliosis

“…These data suggest that following infection, one of the primary cells in brain involved in the induction of neuroborreliosis may be the microglia and that B. burgdorferi induces, at least in part, the innate immune response in brain. Further, these data suggest that treatment of infected rats with prophylactic GTA can reverse the induction of microglia similar to that found in rats subjected to lipopolysaccharide (LPS)-induced neuroinflammation [11,15]. …”

“…In brain, acetate is converted to acetyl coenzyme A (acetyl-CoA) through the combined action of nuclear acetyl-CoA synthetase 1 [12] and mitochondrial acetyl-CoA synthetase 2 [13]. When acetate is supplied by a single oral dose of glyceryl triacetate (GTA), brain acetyl-CoA levels increase by 2.2-fold, it reduces neuroglia activation by 40 to 50% [11], increases histone acetylation [14], and is anti-inflammatory with regard to reducing IL-1β in a rat model of neuroinflammation [15]. Further, in cultured microglia, acetate treatment shifts the release of cytokines to a more anti-inflammatory state through mechanisms that involve both histone and non-histone protein acetylation [16].…”