• Le 17 décembre 2018
    Institut de Recherche en Santé - 8 quai Moncousu - Nantes
    Amphithéâtre Denis Escande
  • 11h00

Rev-erbα: a regulator of circadian physiology

Rev-erbα: a regulator of circadian physiology

Hélène DUEZ, PhD, invited by David Jacobi (Eq V)
Directrice de Recherche (DR2) Inserm & Group leader
UMR1011 Inserm- Institut Pasteur de Lille - Université de Lille - European Genomic Institute for Diabetes (EGID)

helene.duez@pasteur-lille.fr

Abstract

Many physiological processes oscillate diurnally under the control of the biological clock. The pervasive role of the clock in all facets of physiology is illustrated by the fact that disruption of the clock (upon shiftwork, repeated jetlag, chronic exposure to artificial light at night) leads to numerous pathologies ranging from metabolic and cardio-vascular diseases to immune disorders.

The molecular clock is composed of several transcription factors among which the drug-targetable nuclear receptor Rev-erb-α. Rev-erb-α is implicated in the circadian control of hepatic metabolism and Rev-erbα deletion in mice provokes a de-repression of hepatic lipogenesis as well as increased plasma levels of atherogenic lipoprotein particles, contributing to the development of cardiovascular complications. In skeletal muscle, the clock controls metabolism, exercise performance and mass. Indeed, mitochondrial function oscillates throughout the 24h cycle in human myotubes, and oscillations in clock genes are impaired when myotubes are isolated from diabetic patients. We also showed that circadian misalignment in healthy young lean men compromises skeletal muscle insulin sensitivity, suggesting that impaired skeletal muscle clock function may contribute to the increased risk of type 2 diabetes observed in shiftworkers. Among the clock components, Rev-erb-α is important for muscle physiology by regulating both mitochondrial biogenesis and respiration, autophagy and protecting from muscle loss.

Finally, we also discovered that Reverb-α is a major player in the so-called circadian immunity and a pharmacological target for NLRP3-dependent acute and chronic inflammatory disorders. Indeed, Rev-erb-α controls the secretion of pro-inflammatory cytokines in macrophages through rhythmic repression of the NLRP3 inflammasome pathway, and its activation protects from sepsis and fulminant hepatitis.

In conclusion, Rev-erb-α plays a prominent role in the circadian control of metabolism and immunity, and a privileged pharmacological target to restore circadian rhythmicity and mitigate metabolic, cardiovascular and inflammatory disorders.