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Daily liver rhythms: Coupling morphological and molecular oscillations.

Ueli Schibler1, Flore Sinturel2, Felix Naef3

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Keywords:
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Area of Science:

  • Chronobiology
  • Molecular Biology
  • Hepatology

Background:

  • Mammalian physiology is governed by a hierarchical circadian timing system, with the suprachiasmatic nucleus (SCN) as the master pacemaker.
  • The liver, crucial for metabolic adaptation, exhibits daily rhythms in gene expression, protein synthesis, and detoxification.
  • Remarkably, liver mass and hepatocyte morphology oscillate significantly over a 24-hour period.

Purpose of the Study:

  • To investigate the mechanisms underlying the diurnal oscillation of liver mass and hepatocyte size.
  • To explore the role of the actin cytoskeleton and associated signaling pathways in regulating these circadian rhythms.
  • To understand how these cellular changes contribute to the synchronization of liver clocks.

Main Methods:

  • Utilized mouse models to study daily fluctuations in liver mass, hepatocyte size, RNA, and protein accumulation.
  • Analyzed ribosome content and its correlation with protein synthesis rates.
  • Investigated actin cytoskeleton dynamics and its regulation by myocardin-related transcription factors-serum response factor (MRTF-SRF) signaling.

Main Results:

  • Liver mass in mice fluctuates by 30–40% daily, accompanied by rhythmic changes in hepatocyte size and global protein/RNA levels.
  • Ribosome abundance correlates with liver size, acting as a rate-limiting factor for diurnal protein synthesis.
  • Hepatocyte actin cytoskeleton undergoes significant polymerization cycles, with F-actin bundles assembling at night, coinciding with maximal liver size.

Conclusions:

  • Circadian rhythms in liver mass are driven by oscillations in hepatocyte size and ribosome content, impacting protein synthesis.
  • Actin polymerization cycles in hepatocytes are essential for maintaining cellular robustness during size fluctuations.
  • MRTF-SRF signaling, influenced by actin dynamics, plays a role in the circadian transcription of clock genes like Per2, synchronizing liver clocks.