The nuclear receptor REV-ERBα is implicated in the alteration of β-cell autophagy and survival under diabetogenic conditions.
Matthew R BrownDamien LaouteouetMorgane DelobelOrianne VillardChristophe BrocaGyslaine BertrandAnne WojtusciszynStéphane DalleMagalie A RavierAleksey V MatveyenkoSafia CostesPublished in: Cell death & disease (2022)
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.
Keyphrases
- single cell
- cell death
- oxidative stress
- endoplasmic reticulum stress
- signaling pathway
- stem cells
- induced apoptosis
- poor prognosis
- type diabetes
- magnetic resonance
- adipose tissue
- metabolic syndrome
- young adults
- bone marrow
- long non coding rna
- skeletal muscle
- endothelial cells
- small molecule
- cell cycle arrest
- diabetic rats
- protein protein
- pi k akt
- squamous cell
- induced pluripotent stem cells
- pluripotent stem cells