The nuclear receptor REV-ERBα is implicated in the alteration of β-cell autophagy and survival under diabetogenic conditions.
The nuclear receptor REV-ERBα is implicated in the alteration of β-cell autophagy and survival under diabetogenic conditions.
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DOI：
10.1038/s41419-022-04767-z
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发表时间：
2022-04-15
影响因子：
9
通讯作者：
Costes, Safia
中科院分区：
文献类型：
--
作者：
Brown, Matthew R.;Laouteouet, Damien;Delobel, Morgane;Villard, Orianne;Broca, Christophe;Bertrand, Gyslaine;Wojtusciszyn, Anne;Dalle, Stephane;Ravier, Magalie A.;Matveyenko, Aleksey, V;Costes, Safia
2型糖尿病（T2 DM）中的胰腺β细胞衰竭与自噬调节受损相关，自噬通过清除错误折叠的蛋白质和受损的细胞器来控制β细胞发育、功能和存活。然而，T2 DM β细胞中导致缺陷性自噬的机制仍然未知。由于最近的研究发现生物钟转录抑制因子REV-ERBα是一种新的癌症自噬调节因子，在这项研究中，我们开始测试REV-ERBα介导的自噬抑制是否有助于T2 DM中β细胞的衰竭。我们的研究提供了证据表明，常见的糖尿病应激因素（例如，葡萄糖毒性和姜黄素介导的炎症）增加β细胞REV-ERBα表达并损害β细胞自噬和存活。值得注意的是，REV-ERBα的药理学激活显示了致糖尿病应激物通过抑制自噬通量、存活和胰岛素分泌对β细胞的表型效应。相反，REV-ERBα的负调节显示出对炎症和葡萄糖毒性诱导的β细胞衰竭提供部分保护。最后，使用生物信息学方法，我们提供了T2 DM人胰岛中REV-ERBα活性增强与自噬和蛋白降解途径的转录调控受损相关的进一步支持证据。总之，我们的研究揭示了T2 DM中REV-ERBα表达、自噬抑制和β细胞衰竭之间先前未探索的因果关系。
Pancreatic β-cell failure in type 2 diabetes mellitus (T2DM) is associated with impaired regulation of autophagy which controls β-cell development, function, and survival through clearance of misfolded proteins and damaged organelles. However, the mechanisms responsible for defective autophagy in T2DM β-cells remain unknown. Since recent studies identified circadian clock transcriptional repressor REV-ERBα as a novel regulator of autophagy in cancer, in this study we set out to test whether REV-ERBα-mediated inhibition of autophagy contributes to the β-cell failure in T2DM. Our study provides evidence that common diabetogenic stressors (e.g., glucotoxicity and cytokine-mediated inflammation) augment β-cell REV-ERBα expression and impair β-cell autophagy and survival. Notably, pharmacological activation of REV-ERBα was shown to phenocopy effects of diabetogenic stressors on the β-cell through inhibition of autophagic flux, survival, and insulin secretion. In contrast, negative modulation of REV-ERBα was shown to provide partial protection from inflammation and glucotoxicity-induced β-cell failure. Finally, using bioinformatic approaches, we provide further supporting evidence for augmented REV-ERBα activity in T2DM human islets associated with impaired transcriptional regulation of autophagy and protein degradation pathways. In conclusion, our study reveals a previously unexplored causative relationship between REV-ERBα expression, inhibition of autophagy, and β-cell failure in T2DM.
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