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Circadian dysregulation disrupts bile acid homeostasis

Ke Ma1, Rui Xiao, Hsiu-Ting Tseng

  • 1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.

Plos One
|September 1, 2009
PubMed
Abstract

Insights

Disrupting the circadian clock dysregulates bile acid homeostasis, leading to liver damage and cholestasis. This highlights the critical role of daily rhythms in maintaining liver health and bile acid balance.

Area of Science:

  • Hepatology
  • Chronobiology
  • Molecular Biology

Background:

  • Bile acids are toxic compounds regulated by circadian rhythms.
  • Hepatic production, uptake, and export of bile acids are tightly controlled.
  • The impact of circadian clock disruption on bile acid homeostasis was investigated.

Purpose of the Study:

  • To determine how disrupting the peripheral circadian clock affects bile acid homeostasis.
  • To investigate the mechanisms underlying bile acid dysregulation due to circadian disruption.

Main Methods:

  • Utilized restricted feeding to phase-shift peripheral clocks in mice.
  • Employed genetic ablation of Per1 and Per2 genes (PERDKO mice).
  • Monitored bile acid levels, liver enzymes (AST), and expression of key bile acid synthesis/transport genes (Cyp7A1, NTCP).

Main Results:

  • Both restricted feeding and PERDKO disrupted bile acid control, causing hepatic cholestasis.
  • Restricted feeding led to transiently elevated hepatic bile acids, CAR/PXR activation, and increased AST.
  • PERDKO mice showed elevated serum bile acids and lost circadian expression of Cyp7A1 and NTCP, linked to blunted DBP expression.

Conclusions:

  • Disruption of the circadian clock dysregulates bile acid homeostasis.
  • Circadian clock disruption mimics cholestatic liver disease.
  • Daily rhythms are crucial for maintaining bile acid balance and liver function.

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