Dietary proanthocyanidins modulate the rhythm of BMAL1 expression and induce RORα transactivation in HepG2 cells

• A grape seed PA extract (GSPE) modulates the clock rhythm in liver.
• We studied the molecular mechanism by which GSPE entrains the clock in vitro.
• GSPE overexpresses BMAL1 strongly and very quickly in HepG2.
• GSPE activates RORα, suggesting its implication on BMAL1 modulation.
• Melatonin reproduces the effect on BMAL1, but acting through MT1 receptor.

Proanthocyanidins (PAs), a flavonoid sub-class, alter the expression of clock genes in the liver of lean and obese rats. The present study aimed to determine whether PAs could modulate the 24-hour rhythmicity of clock gene expression and to identify the molecular mechanism through which PAs could adjust the clock system in HepG2 cells. The 24-hour rhythmicity of core clock (CLOCK and BMAL1) and clock-controlled (CRY, PER2, RORα, REV-ERBα) gene expression indicated that a grape seed proanthocyanidin extract (GSPE) shifted the acrophase of nearly all of them, but BMAL1 appeared as the most sensitive gene to GSPE. Specifically, GSPE increased BMAL1 expression strongly and very quickly. This effect was also reproduced by melatonin. The overexpression of BMAL1 was melatonin receptor 1 (MT1) dependent for melatonin but MT1 independent for GSPE. However, GSPE increased the transcriptional activity of RORα, suggesting that this nuclear receptor could be responsible for the modulation of BMAL1 by GSPE.