The Role of Butyrate as a Histone Deacetylase Inhibitor in Protecting Pancreatic Beta Cells from IL-1ß-Induced Dysfunction
Butyrate, a gut microbial metabolite, has beneficial effects on glucose homeostasis and has become an attractive drug target for type 2 diabetes (T2D). Recently, we showed that butyrate protects pancreatic beta cells against cytokine-induced dysfunction. In this study, we explored the underlying mechanisms of butyrate action. Pancreatic islets were exposed to a non-cytotoxic concentration of interleukin 1ß (IL-1ß) for ten days to mimic the low-grade inflammation in T2D. An isoform-selective histone deacetylase 3 (HDAC3) inhibitor normalized IL-1ß-reduced GSIS and insulin content similar to the effect of butyrate. In contrast, FFAR2/3 agonists failed to normalize IL-1ß-induced impairment of GSIS and reduced insulin content. Butyrate, irrespective of IL-1ß, inhibited HDAC activity and increased histone H3 and H4 acetylation by 3- and 10-fold, respectively. Genome-wide analysis of histone H3K27 acetylation (H3K27ac) revealed that butyrate mainly increased H3K27ac at promoter regions (~68 %), while H3K27ac peaks regulated by IL-1ß were more equally distributed at promoters (~33 %), introns (~23 %) and intergenic regions (~23 %). Gene ontology analysis showed that butyrate increased IL-1ß-reduced H3K27ac  levels near several genes related to hormone secretion and reduced IL-1ß-increased H3K27ac levels  near genes associated with inflammatory responses . Butyrate alone increased H3K27ac near many genes related to MAPK signaling, hormone secretion and differentiation, and decreased H3K27ac at genes involved in cell replication. Together, these results suggest that butyrate prevents IL-1ß-induced beta cell dysfunction by inhibition of HDACs resulting in changes in H3K27ac levels at genes relevant for beta cell function and inflammatory responses. Overall design: Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for histone variant H3K27ac in mouse pancreas.