The long non-coding RNA βFaar regulates islet β-cell function and survival during obesity in mice

Fangfang Zhang, Yue Yang, Xi Chen, Yue Liu, Qianxing Hu, Bin Huang, Yuhong Liu, Yi Pan, Yanfeng Zhang, Dechen Liu, Rui Liang, Guoqing Li, Qiong Wei (), Ling Li () and Liang Jin ()
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Fangfang Zhang: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University
Yue Yang: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University
Xi Chen: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University
Yue Liu: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University
Qianxing Hu: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University
Bin Huang: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University
Yuhong Liu: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University
Yi Pan: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University
Yanfeng Zhang: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University
Dechen Liu: Zhongda Hospital, School of Medicine, Southeast University
Rui Liang: Organ Transplant Center, Tianjin First Central Hospital, Nankai University
Guoqing Li: Zhongda Hospital, School of Medicine, Southeast University
Qiong Wei: Zhongda Hospital, School of Medicine, Southeast University
Ling Li: Zhongda Hospital, School of Medicine, Southeast University
Liang Jin: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-24302-6

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