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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Acetate, the key modulator of inflammatory responses in acute alcoholic hepatitis.
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Acetate, the key modulator of inflammatory responses in acute alcoholic hepatitis.

机译：乙酸盐，急性酒精性肝炎中炎症反应的关键调节剂。

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Acute alcoholic hepatitis is characterized by disproportionate macrophage inflammatory cytokine responses to bacterial lipopolysaccharide. Lack of knowledge of the underlying mechanism has limited progress toward effective therapy. We postulated a novel mechanism by which ethanol increases histone acetylation, increasing proinflammatory gene transcription and cytokine synthesis. Cytokine responses to lipopolysaccharide in a human macrophage cell line cultured in 86 mM ethanol, 1 mM acetate, and normal media were measured by multiplex immunoassay. Changes in histone acetylation were determined by immunofluorescence microscopy and chromatin immunoprecipitation on presentation. The effect of ethanol and acetate on acetyl-coenzyme A (acetyl-coA) synthetases, which convert acetate to acetyl-coA, the substrate for histone acetylation, was determined by quantitative reverse-transcription polymerase chain reaction and immunoblotting. Knockdown of acetyl-coA synthetases by short hairpin RNA (shRNA) was used to determine their role in ethanol's enhancement of the inflammatory cytokine response. Ethanol-exposed macrophages developed enhanced interleukin 6 (IL6), IL8, and tumor necrosis factor alpha responses to lipopolysaccharide with time-dependent increases in histone acetylation that could be prevented by inhibition of ethanol metabolism. Chromatin immunoprecipitation confirmed increased histone acetylation at promoter regions of specific cytokine genes. The effect of ethanol was reproduced by incubation with acetate, the principal hepatic metabolite of ethanol, and both ethanol and acetate reduced histone deacetylase activity and up-regulated acetyl-coA synthetases. Knockdown of the acetyl-coA synthetases abrogated the effect of ethanol on cytokine production. CONCLUSION: Synthesis of metabolically available acetyl-coA from acetate is critical to the increased acetylation of proinflammatory gene histones and consequent enhancement of the inflammatory response in ethanol-exposed macrophages. This mechanism is a potential therapeutic target in acute alcoholic hepatitis.
机译：急性酒精性肝炎的特征是巨噬细胞对细菌脂多糖的炎症细胞因子反应异常。缺乏对潜在机制的了解，限制了有效治疗的进展。我们提出了一种新的机制，乙醇可以通过该机制增加组蛋白乙酰化，增加促炎基因转录和细胞因子合成。通过多重免疫测定法测量了在86 mM乙醇，1 mM乙酸盐和正常培养基中培养的人巨噬细胞系中细胞因子对脂多糖的反应。组蛋白乙酰化的变化通过免疫荧光显微镜和染色质免疫沉淀法测定。通过定量逆转录聚合酶链反应和免疫印迹法测定了乙醇和乙酸盐对乙酰辅酶A（乙酰辅酶A）合成酶的影响，该酶将乙酸盐转化为组蛋白乙酰化的底物乙酰辅酶A。通过短发夹RNA（shRNA）敲除乙酰辅酶A合成酶来确定其在乙醇增强炎症细胞因子反应中的作用。暴露于乙醇的巨噬细胞可增强白介素6（IL6），IL8和肿瘤坏死因子对脂多糖的反应，并具有组蛋白乙酰化的时间依赖性增加，可通过抑制乙醇代谢来防止。染色质免疫沉淀证实在特定细胞因子基因的启动子区域组蛋白乙酰化增加。乙醇的作用是通过与乙酸盐（乙醇的主要肝脏代谢产物）一起温育来实现的，并且乙醇和乙酸盐都降低了组蛋白脱乙酰基酶的活性并上调了乙酰辅酶A的合成。击倒乙酰辅酶A合成酶消除了乙醇对细胞因子产生的影响。结论：从乙酸酯合成可代谢的乙酰辅酶A对增加促炎基因组蛋白的乙酰化以及因此增强暴露于乙醇的巨噬细胞的炎症反应至关重要。该机制是急性酒精性肝炎的潜在治疗靶标。

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