Circadian dysregulation disrupts bile acid homeostasis.
BACKGROUND
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.


RESULTS
Both restricted feeding, which phase shifts peripheral clocks, and genetic ablation in Per1(-/-)/Per2(-/-) (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.


CONCLUSIONS
We conclude that disruption of the circadian clock results in dysregulation of bile acid homeostasis that mimics cholestatic disease.
Ma
Ke
K
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
Xiao
Rui
R
Tseng
Hsiu-Ting
HT
Shan
Lu
L
Fu
Loning
L
Moore
David D
DD
D000818:Animals; D001219:Aspartate Aminotransferases / Q000235:genetics; D001647:Bile Acids and Salts / Q000502:physiology*; D002940:Circadian Rhythm; D006706:Homeostasis; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D056950:Period Circadian Proteins / Q000235:genetics / Q000502:physiology
D001647:Bile Acids and Salts; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D001219:Aspartate Aminotransferases