Journal
CANCER CELL
Volume 30, Issue 6, Pages 909-924Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2016.10.007
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Funding
- NIH/NCI [R01 CA137019-01A, P30CA125123]
- USDA/ARS [6250-51000-055]
- CRPIT [MIRA RP150587]
- NIH/NIDDK [R01 DK46546, 5T32 DK007696-20, R01CA137019-05S]
- R.P. Doherty, Jr. Welch Chair in Science [Q-0022]
- Public Health Service Grant [DK56338]
- CPRIT Core Facility Support Award [RP120092]
- NCI Shared Resources funds [2P30CA125123-09]
- BCM Dan L. Duncan Cancer Center
- NSF [DMS-1161759]
- Alkek Center for Molecular Discovery
- BCM Agilent Technologies Center of Excellence
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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.
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