Epithelial cell adhesion molecule expression in hepatic stem/progenitor cells is controlled by the molecular clock system

The circadian rhythm, which regulates various body functions, is transcriptionally controlled by a series of clock gene clusters. The clock genes are related to the pathology of various kinds of diseases. Although there is evidence of serious sleep disorders in patients with chronic hepatitis, the liver regeneration mechanism under chronic hepatitis conditions and its association with the clock genes are not clear. In this study, the influence of the circadian locomotor output cycles kaput (CLOCK), which is one of the clock genes, on a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced hepatitis animal model was investigated. The appearance of potential hepatic stem-like cells (epithelial cell adhesion molecule [EpCAM]-positive cells) is an initial critical step in liver regeneration during chronic inflammation. The results showed a considerable number of hepatic EpCAM-positive cells in the wild-type (WT) mice 1 week after the DDC feeding. However, the number of EpCAM-positive cells in the Clock-mutant (Clk/Clk) mice decreased, and their hepatitis was worse compared with the WT mice. In addition, the expression of Epcam mRNA, which is a functional marker of potential hepatic stem-like cells, was controlled by LEF1, which was regulated by CLOCK. The results of this study will facilitate the elucidation of the liver regeneration mechanisms, including those at the molecular level, and may assist in the development of new treatment modalities in the future.