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eMediNexus 14 January 2022
Acute alcoholic hepatitis causes unbalanced macrophage inflammatory cytokine responses to bacterial lipopolysaccharide. Lack of knowledge of the underlying mechanism has restricted the invention of effective therapy. A study hypothesized a novel mechanism that causes ethanol to boost histone acetylation, augmenting proinflammatory gene transcription and cytokine synthesis.
Human macrophage cell lines cultured in 86 mM ethanol, 1 mM acetate, and normal media were assessed for their Cytokine responses to lipopolysaccharide by multiplex immunoassay. immunofluorescence microscopy and chromatin immunoprecipitation were utilized to determine any Shifts in histone acetylation. Quantitative reverse-transcription polymerase chain reaction and immunoblotting were utilized to assess the impact of ethanol and acetate on acetyl-coenzyme A (acetyl-coA) synthetases, which convert acetate to acetyl-coA, the substrate for histone acetylation.
Downregulation of acetyl-coA synthetases by short hairpin RNA (shRNA) was used to determine their role in increased inflammatory cytokine response caused by ethanol.
The following observations were made-
Thus the synthesis of metabolically available acetyl-coA from acetate is crucial to enhance the acetylation of proinflammatory gene histones and the resultant increase of the inflammatory response in ethanol-exposed macrophages. This mechanism can serve as a potential therapeutic target for managing acute alcoholic hepatitis.
SOURCE- Kendrick SFW, OBoyle G, Mann J, Zeybel M, Palmer J, Jones DEJ, Day CP. Acetate, the key modulator of inflammatory responses in acute alcoholic hepatitis, Hepatology, 2010;51(6):1988-1997. https://doi.org/10.1002/hep.23572
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