title: Circadian dysregulation disrupts bile acid homeostasis.
abstract: 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.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Ke
authors.initials: K
authors.lastname: Ma
authors.forename: Rui
authors.initials: R
authors.lastname: Xiao
authors.forename: Hsiu-Ting
authors.initials: HT
authors.lastname: Tseng
authors.forename: Lu
authors.initials: L
authors.lastname: Shan
authors.forename: Loning
authors.initials: L
authors.lastname: Fu
authors.forename: David D
authors.initials: DD
authors.lastname: Moore
mesh_terms: 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
chemical_list: D001647:Bile Acids and Salts; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D001219:Aspartate Aminotransferases