TY - JOUR
T1 - The nuclear receptor REV-ERBα is implicated in the alteration of β-cell autophagy and survival under diabetogenic conditions
AU - Brown, Matthew R.
AU - Laouteouet, Damien
AU - Delobel, Morgane
AU - Villard, Orianne
AU - Broca, Christophe
AU - Bertrand, Gyslaine
AU - Wojtusciszyn, Anne
AU - Dalle, Stéphane
AU - Ravier, Magalie A.
AU - Matveyenko, Aleksey V.
AU - Costes, Safia
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/4
Y1 - 2022/4
N2 - 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.
AB - 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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U2 - 10.1038/s41419-022-04767-z
DO - 10.1038/s41419-022-04767-z
M3 - Article
C2 - 35428762
AN - SCOPUS:85128403126
SN - 2041-4889
VL - 13
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 4
M1 - 353
ER -