UELI SCHIBLER, UNIVERSITY OF GENEVASeveral years ago and somewhat by accident, researchers led by Ueli Schibler, now professor emeritus at the University of Geneva in Switzerland, noticed that mouse liver cells are larger toward the end of the night and smaller at the end of the day. In a study published today (May 4) in Cell, the group has not only confirmed that hepatocyte size oscillates daily, but that the entire liver is larger at night when mice are most active. The observed changes in cell and organ size are related to feeding-fasting cycles and are accompanied by increased protein levels and ribosome assembly.
“This is fundamental work,” Carrie Partch of the University of California, Santa Cruz, who was not involved in the study told The Scientist. “The ribosome is this universal machine, and the thought that you have a clock controlling its assembly and tuning when it’s most active is really exciting.”
Schibler and colleagues determined that hepatocyte size swelled throughout night then shrunk during the day. But they only observed this oscillation when they fed the mice at night. When mice were fed during the day, when they are less active, that clear rhythm disappeared, even though the animals ate similar amounts of food.
These cellular cycles appeared to affect the liver as a whole. At the end of the animals’ active period, the livers of night-fed mice were nearly 50 percent larger—as a percentage of total body weight—than after their inactive period. The researchers did not see this pattern in the livers of day-fed mice or in other organs.
A similar pattern emerged when the research team investigated RNA and protein abundances, both of which rose throughout the active phase in night-fed rodents. In contrast, levels of RNA and protein did not change in day-fed mice. DNA levels stayed constant in all animals, indicating that liver cell number does not vary diurnally.
“We think about the liver as having a fairly constant size, but this paper clearly shows that liver size has a circadian rhythm,” said Mitchell Lazar of the University of Pennsylvania who did not participate in the work. “There will be a lot of interest in this phenomenon . . . and what causes it.”
The researchers found that translation efficiency increased midway through the active period in night-fed mice and that ribosomes accumulated in hepatocytes, peaking at the end of the night. Pre-messenger RNA and pre-ribosomal RNA (rRNA) synthesis remained constant over 24 hours, however, suggesting that the rhythm of rRNA accumulation is controlled posttranscriptionally—likely by degradation of ribosomes during the day. Indeed, Schibler’s group found that one rRNA precursor is polyadenylated in a circadian fashion and targeted to the 3’-5’ nuclear exosome complex for destruction.
Surprisingly, when the researchers examined polyadenylation of 18S rRNA precursor in the livers of mice with a gene controlling central circadian rhythms knocked out, the diurnal oscillations didn’t change much. This finding suggests that feeding-fasting cycles play a more important role than the master clock in directing rRNA polyadenylation and ribosome accumulation.
“We have no idea how the light cycle cooperates with the feeding cycle,” Schibler said. “What’s probably more difficult, but also important, is to figure out the function of” these rhythms.
“It’s very likely that this mechanism is also relevant in humans,” he added. Schibler hypothesized that the detoxification function of the liver is influenced by the organ’s circadian rhythms, a possibility that could have implications for the efficacy of drugs processed through the liver. “I think this has a really significant future,” he said. “More people should know about it and more people should work on it.”
F. Sinturel et al., “Diurnal oscillations in liver mass and cell size accompany ribosome assembly cycles,” Cell, doi:10.1016/j.cell.2017.04.015, 2017.