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-

• Ethanol-exposed macrophages had increased responses of interleukin 6 (IL6), IL8, and tumor necrosis factor-alpha to lipopolysaccharide with increases in histone acetylation (time-dependent) that could be stopped by inhibiting ethanol metabolism. 
• Augmented histone acetylation at promoter regions of specific cytokine genes was proved by Chromatin immunoprecipitation. 
• Acetate incubation duplicated the ethanol effect, and both decreased histone deacetylase activity and up-regulated acetyl-coA synthetases. 
• Restricting acetyl-coA synthetases, rescued ethanol from cytokine production. 

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