State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, China.
Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu Province, China.
Nat Commun. 2021 Jun 28;12(1):3997. doi: 10.1038/s41467-021-24302-6.
Despite obesity being a predisposing factor for pancreatic β-cell dysfunction and loss, the mechanisms underlying its negative effect on insulin-secreting cells remain poorly understood. In this study, we identify an islet-enriched long non-coding RNA (lncRNA), which we name β-cell function and apoptosis regulator (βFaar). βFaar is dramatically downregulated in the islets of the obese mice, and a low level of βFaar is necessary for the development of obesity-associated β-cell dysfunction and apoptosis. Mechanistically, βFaar promote the synthesis and secretion of insulin by upregulating islet-specific genes Ins2, NeuroD1, and Creb1 through sponging miR-138-5p. In addition, using quantitative mass spectrometry, we identify TRAF3IP2 and SMURF1 as interacting proteins that are specifically associated with βFaar. We demonstrate that SMURF1 ubiquitin ligase activity is essential for TRAF3IP2 ubiquitination and activation of NF-κB-mediate β-cell apoptosis. Our experiments provide direct evidence that dysregulated βFaar contributes to the development of obesity-induced β-cell injury and apoptosis.
尽管肥胖是导致胰腺β细胞功能障碍和丧失的一个易感因素，但肥胖对胰岛素分泌细胞产生负面影响的机制仍知之甚少。在这项研究中，我们鉴定了一种胰岛丰富的长非编码 RNA（lncRNA），我们将其命名为β细胞功能和凋亡调节因子（βFaar）。βFaar 在肥胖小鼠的胰岛中显著下调，而低水平的βFaar是肥胖相关β细胞功能障碍和凋亡发展所必需的。在机制上，βFaar 通过海绵吸附 miR-138-5p 来上调胰岛特异性基因 Ins2、NeuroD1 和 Creb1，从而促进胰岛素的合成和分泌。此外，我们通过定量质谱分析，鉴定出 TRAF3IP2 和 SMURF1 是与βFaar特异性相关的相互作用蛋白。我们证明了 SMURF1 泛素连接酶活性对于 TRAF3IP2 的泛素化和 NF-κB 介导的β细胞凋亡的激活是必不可少的。我们的实验提供了直接证据，表明失调的βFaar 导致肥胖诱导的β细胞损伤和凋亡的发展。
