Location: Children's Nutrition Research CenterTitle: Circadian dysregulation disrupts bile acid homeostasis Author
Submitted to: PLoS One
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/2/2009
Publication Date: 8/31/2009
Citation: Ma, K., Xiao, R., Tseng, H., Shan, L., Fu, L., Moore, D.D. 2009. Circadian dysregulation disrupts bile acid homeostasis. PLoS One. 4(8): e6843. Interpretive Summary: Recent studies have revealed that disruption of circadian rhythm increases tumor development in both humans and animal models. However, it remains unclear why disruption of circadian rhythm may lead to tumorigenesis. We have found recently, that the circadian clock controls the homeostasis of cell proliferation in vivo, by rhythmically pacing extracellular mitogenic signals that drive the circadian expression of key cell cycle regulators. Loss of function circadian genes in peripheral tissues or disruption of circadian rhythm by jet-lag, disrupts the homeostasis of extracellular signaling, abolishes the circadian rhythm in cell proliferation, and induces tumor development in mice. Our studies indicate that tumor suppression in vivo is a clock-controlled physiological function, and that frequent disruption of circadian rhythm should be considered as an important tumor promoting factor.
Technical Abstract: Bile acids are potentially toxic compounds and their levels of hepatic production, uptake, and export are tightly regulated by many inputs, including circadian rhythm. We tested the impact of disrupting the peripheral circadian clock on integral steps of bile acid homeostasis. Both restricted feeding, which phase shifts peripheral clocks, and genetic ablation in Per12/2/Per22/2 (PERDKO) mice, disrupted normal bile acid control, and resulted in hepatic cholestasis. Restricted feeding caused a dramatic, transient elevation in hepatic bile acid levels that was associated with activation of the xenobiotic receptors CAR and PXR and elevated serum aspartate aminotransferase (AST), indicative of liver damage. In the PERDKO mice, serum bile acid levels were elevated and the circadian expression of key bile acid synthesis and transport genes, including Cyp7A1 and NTCP, was lost. This was associated with blunted expression of a primary clock output, the transcription factor DBP, which transactivates the promoters of both genes. We conclude that disruption of the circadian clock results in dysregulation of bile acid homeostasis that mimics cholestatic disease.