BET bromodomain proteins Brd2, Brd3 and Brd4 selectively regulate metabolic pathways in the pancreatic ß-cell

Displacement of Bromodomain and Extra-Terminal (BET) proteins from chromatin has promise for cancer and inflammatory disease treatments, but roles of BET proteins in metabolic disease remain unexplored. Small molecule BET inhibitors, such as JQ1, block BET protein binding to acetylated lysines, but lack selectivity within the BET family (Brd2, Brd3, Brd4, Brdt), making it difficult to disentangle contributions of each family member to transcriptional and cellular outcomes. Here, we demonstrate multiple improvements in pancreatic ß-cells upon BET inhibition with JQ1 or BET-specific siRNAs. JQ1 (50-400 nM) increases insulin secretion from INS-1 cells in a concentration dependent manner. JQ1 increases insulin content in INS-1 cells, accounting for increased secretion, in both rat and human islets. Higher concentrations of JQ1 decrease intracellular triglyceride stores in INS-1 cells, a result of increased fatty acid oxidation. Specific inhibition of both Brd2 and Brd4 enhances insulin transcription, leading to increased insulin content. Inhibition of Brd2 alone increases fatty acid oxidation. Overlapping yet discrete roles for individual BET proteins in metabolic regulation suggest new isoform-selective BET inhibitors may be useful to treat insulin resistant/diabetic patients. Results imply that cancer and diseases of chronic inflammation or disordered metabolism are related through shared chromatin regulatory mechanisms.溴结构域额外末端结构域（Bromodomain and Extra-Terminal, BET）蛋白从染色质上的解离，在癌症与炎症性疾病治疗中展现出应用潜力，但BET蛋白在代谢性疾病中的作用仍未得到探索。小分子BET抑制剂（如JQ1）可阻断BET蛋白与乙酰化赖氨酸的结合，但在BET家族（Brd2、Brd3、Brd4、Brdt）内缺乏选择性，这使得难以厘清每个家族成员对转录及细胞结局的具体贡献。本研究证实，使用JQ1或BET特异性小干扰RNA（small interfering RNA, siRNA）抑制BET蛋白后，胰腺β细胞可出现多项改善。JQ1（50~400 nM）可浓度依赖性地提升INS-1细胞的胰岛素分泌水平。在大鼠胰岛与人类胰岛中，JQ1均可增加INS-1细胞的胰岛素含量，而这一变化正是其分泌水平升高的原因。较高浓度的JQ1会减少INS-1细胞内的甘油三酯储存，这一现象源于脂肪酸氧化水平的提升。同时特异性抑制Brd2与Brd4可增强胰岛素转录，进而提升胰岛素含量。仅特异性抑制Brd2即可提升脂肪酸氧化水平。单个BET蛋白在代谢调控中既存在功能重叠又具有各自独特的作用，这提示新型亚型选择性BET抑制剂或可用于治疗胰岛素抵抗/糖尿病患者。本研究结果表明，癌症、慢性炎症性疾病以及代谢紊乱性疾病可通过共有的染色质调控机制相互关联。