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The hepatocyte clock and feeding control chronophysiology of multiple liver cell types

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Science  11 Sep 2020:
Vol. 369, Issue 6509, pp. 1388-1394
DOI: 10.1126/science.aba8984

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Keeping rhythm requires communication

In mammals, daily cycles in physiology require the synchronized activity of circadian clocks in peripheral organs such as the liver, a hub of metabolism. Guan et al. generated mice with hepatocytes that lack two transcriptional repressors known to be essential for clock function. This experimental manipulation unexpectedly disrupted rhythmic gene expression and metabolism not only in hepatocytes but also in other liver cell types. Feeding behavior also coregulated circadian rhythms in multiple liver cell types. Cell-cell communication thus appears to be important in maintaining the robustness of peripheral circadian clocks.

Science, this issue p. 1388

Abstract

Most cells of the body contain molecular clocks, but the requirement of peripheral clocks for rhythmicity and their effects on physiology are not well understood. We show that deletion of core clock components REV-ERBα and REV-ERBβ in adult mouse hepatocytes disrupts diurnal rhythms of a subset of liver genes and alters the diurnal rhythm of de novo lipogenesis. Liver function is also influenced by nonhepatocytic cells, and the loss of hepatocyte REV-ERBs remodels the rhythmic transcriptomes and metabolomes of multiple cell types within the liver. Finally, alteration of food availability demonstrates the hierarchy of the cell-intrinsic hepatocyte clock mechanism and the feeding environment. Together, these studies reveal previously unsuspected roles of the hepatocyte clock in the physiological coordination of nutritional signals and cell-cell communication controlling rhythmic metabolism.

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