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

Guan, Dongyin; Xiong, Ying; Trinh, Trang Minh; Xiao, Yang; Hu, Wenxiang; Jiang, Chunjie; Dierickx, Pieterjan; Jang, Cholsoon; Rabinowitz, Joshua D; Lazar, Mitchell A

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. Here we show that deletion of core clock components REV-ERBα and β in adult mouse hepatocytes disrupted diurnal rhythms of a subset of liver genes and altered the diurnal rhythm of de novo lipogenesis. Liver function is also influenced by non-hepatocytic cells, and the loss of hepatocyte REV-ERBs remodeled the rhythmic transcriptomes and metabolomes of multiple cell types within the liver. Finally, alteration of food availability demonstrated 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.