Genetic and epigenetic determinants of alcoholic liver disease

Abstract

Alcoholic liver disease (ALD) is a significant and growing global health problem, responsible for over 10000 deaths per year in the UK alone. Clinical liver failure can result from gradual, chronic depletion of the hepatocyte pool and replacement with fibrous tissue in cirrhosis or from rapid, acute hepatocellular dysfunction secondary to inflammation in acute alcoholic hepatitis (AAH) which carries a mortality of up to 35% on first presentation. Corticosteroid therapy has shown some benefit in AAH but its utility is limited by uncertainty in patient selection and poor clinical response in a proportion of cases. Our current understanding of AAH pathogenesis attributes hepatocellular dysfunction to the action of supra-physiological concentrations of proinflammatory cytokines. Evidence from animal and human studies suggests that the major source of cytokine release is the hepatic macrophage or Kupffer cell responding to an increased concentration of bacterial endotoxin in portal blood following an ethanol-mediated increase in gut permeability. However, this enhanced and sustained inflammatory response is at odds with the normal response in the liver in which endotoxin tolerance allows bacterial components to be cleared from the blood without an inflammatory response. This study set out to investigate factors that determine the enhanced inflammatory response in AAH and its response to therapy. Genetic analysis revealed a single nucleotide polymorphism in a component of the endotoxin response pathway (the Toll-like receptor adapter molecule MAL) associated weakly with advanced disease in both ALD and the related condition non-alcoholic steatohepatitis. Different alleles associated with advanced disease in the two conditions, suggesting divergent importance of signalling pathways in their pathogenesis. Assays in AAH patients demonstrated that their lymphocyte steroid sensitivity was impaired relative to normal controls, correlated with clinical markers of steroid responsiveness, improved in recovery and could be improved by ex vivo supplementation with theophylline, a known recruiter of histone deacetylases. The role of histone modifications in the enhancement of inflammatory responses in ethanol was investigated in a human macrophage cell-line model which revealed increased histone acetylation at pro-inflammatory cytokine gene promoter regions associated with potentiated cytokine responses to endotoxin after culture in ethanol or its metabolite acetate. This effect was abrogated by knockdown of acetyl-coA synthetases, suggesting that increased synthesis of acetyl-coA from acetate is crucial for histone acetylation and consequent increased cytokine production after ethanol exposure. These findings suggest that while genetic predisposition may have some effect on innate immune responses in the pathogenesis of alcoholic liver disease, the more significant contribution is likely to come from gene-environment interactions such as modulation of histone acetylation by products of ethanol metabolism. This epigenetic relationship between metabolism and gene expression in inflammation, mediated by histone deacetylases such as the sirtuin proteins, may be a novel therapeutic target in ALD and potentially also in other inflammatory conditions.