The nuclear receptor REV-ERBα is implicated in the alteration of β-cell autophagy and survival under diabetogenic conditions - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Cell Death and Disease Année : 2022

The nuclear receptor REV-ERBα is implicated in the alteration of β-cell autophagy and survival under diabetogenic conditions

Matthew Brown
Aleksey Matveyenko
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Résumé

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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hal-03647414 , version 1 (02-06-2022)

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Matthew Brown, Damien Laouteouet, Morgane Delobel, Orianne Villard, Christophe Broca, et al.. The nuclear receptor REV-ERBα is implicated in the alteration of β-cell autophagy and survival under diabetogenic conditions. Cell Death and Disease, 2022, 13 (4), pp.353. ⟨10.1038/s41419-022-04767-z⟩. ⟨hal-03647414⟩
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