Abstract
Chronic jet lag induces spontaneous hepatocellular carcinoma (HCC) in wild-type mice following a mechanism very similar to that observed in obese humans. The process initiates with non-alcoholic fatty liver disease (NAFLD) that progresses to steatohepatitis and fibrosis before HCC detection. This pathophysiological pathway is driven by jet-lag-induced genome-wide gene deregulation and global liver metabolic dysfunction, with nuclear receptor-controlled cholesterol/bile acid and xenobiotic metabolism among the top deregulated pathways. Ablation of farnesoid X receptor dramatically increases enterohepatic bile acid levels and jet-lag-induced HCC, while loss of constitutive androstane receptor (CAR), a well-known liver tumor promoter that mediates toxic bile acid signaling, inhibits NAFLD-induced hepatocarcinogenesis. Circadian disruption activates CAR by promoting cholestasis, peripheral clock disruption, and sympathetic dysfunction.
Original language | English (US) |
---|---|
Pages (from-to) | 909-924 |
Number of pages | 16 |
Journal | Cancer cell |
Volume | 30 |
Issue number | 6 |
DOIs | |
State | Published - Dec 12 2016 |
Keywords
- cholestasis
- chronic circadian disruption
- constitutive androstane receptor (CAR)
- farnesoid X receptor (FXR)
- fibrosis
- hepatocarcinogenesis
- non-alcoholic fatty liver disease
- non-alcoholic steatohepatitis
- social jet lag
- sympathetic dysfunction
ASJC Scopus subject areas
- Oncology
- Cell Biology
- Cancer Research