Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
FEBS J. 2024 Feb;291(3):566-583. doi: 10.1111/febs.17005. Epub 2023 Nov 28.
Butyrate, a gut microbial metabolite, has beneficial effects on glucose homeostasis and has become an attractive drug candidate 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 mouse islets were exposed to a non-cytotoxic concentration of interleukin-1β (IL-1β) for 10 days to mimic low-grade inflammation in T2D. Similar to the effect of butyrate, an isoform-selective histone deacetylase 3 (HDAC3) inhibitor normalized IL-1β-reduced glucose-stimulated insulin secretion and insulin content. In contrast, free fatty acid receptor 2 and 3 (FFAR2/3) agonists failed to normalize IL-1β-induced beta cell dysfunction. Furthermore, butyrate inhibited HDAC activity and increased the acetylation of histone H3 and H4 by 3- and 10-fold, respectively. Genome-wide analysis of histone H3 lysine 27 acetylation (H3K27ac) revealed that butyrate mainly increased H3K27ac at promoter regions (74%), while H3K27ac peaks regulated by IL-1β were more equally distributed at promoters (38%), introns (23%) and intergenic regions (23%). Gene ontology analysis showed that butyrate increased IL-1β-reduced H3K27ac levels near several genes related to hormone secretion and reduced IL-1β-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-1β-induced pancreatic islet dysfunction by inhibition of HDACs resulting in changes in H3K27ac levels at genes relevant for beta cell function and inflammatory responses.
丁酸盐是一种肠道微生物代谢产物，对葡萄糖稳态具有有益影响，已成为 2 型糖尿病（T2D）有吸引力的药物候选物。最近，我们表明丁酸盐可保护胰岛β细胞免受细胞因子诱导的功能障碍。在这项研究中，我们探讨了丁酸盐作用的潜在机制。将胰岛暴露于非细胞毒性浓度的白细胞介素-1β（IL-1β）中 10 天，以模拟 T2D 中的低度炎症。与丁酸盐的作用相似，组蛋白去乙酰化酶 3（HDAC3）的同工型选择性抑制剂使 IL-1β降低的葡萄糖刺激的胰岛素分泌和胰岛素含量正常化。相比之下，游离脂肪酸受体 2 和 3（FFAR2/3）激动剂未能使 IL-1β诱导的β细胞功能障碍正常化。此外，丁酸盐抑制 HDAC 活性并使组蛋白 H3 和 H4 的乙酰化分别增加 3 倍和 10 倍。组蛋白 H3 赖氨酸 27 乙酰化（H3K27ac）的全基因组分析表明，丁酸盐主要增加启动子区域的 H3K27ac（74％），而由 IL-1β调节的 H3K27ac 峰在启动子（38％）、内含子（23％）和基因间区域（23％）中的分布更为均匀。基因本体论分析表明，丁酸盐增加了与激素分泌有关的几个基因附近的 IL-1β降低的 H3K27ac 水平，并降低了与炎症反应相关的基因附近的 IL-1β增加的 H3K27ac 水平。丁酸盐本身增加了许多与 MAPK 信号、激素分泌和分化相关的基因附近的 H3K27ac 水平，并降低了与细胞复制相关的基因的 H3K27ac 水平。综上所述，这些结果表明，丁酸盐通过抑制 HDAC 来防止 IL-1β诱导的胰岛功能障碍，导致与β细胞功能和炎症反应相关的基因的 H3K27ac 水平发生变化。
