circadian dysregulation disrupts bile acid homeostasis生理失调会影响胆汁酸体内平衡.pdfVIP

Circadian Dysregulation Disrupts Bile Acid Homeostasis 1 1 1¤a 1¤b 2 1 Ke Ma , Rui Xiao , Hsiu-Ting Tseng , Lu Shan , Loning Fu , David D. Moore * 1 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America, 2 Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America 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. Methodology/Principal Findings: Both restricted feeding, which phase shifts peripheral clocks, and genetic ablation in Per12/ 2 2/ 2 /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/Significance: We conclude that disruption of the circadian clock results in dysregulation of