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Cancer Cell. 2016 Dec 12;30(6):909-924. doi: 10.1016/j.ccell.2016.10.007. Epub 2016 Nov 23.

Circadian Homeostasis of Liver Metabolism Suppresses Hepatocarcinogenesis.

Author information

1
Department of Pediatrics/U.S. Department of Agriculture/Agricultural Research Service/Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
2
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
3
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA.
4
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
5
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
6
Program in Neuroscience, Florida State University, College of Medicine, Tallahassee, FL 32306, USA.
7
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: moore@bcm.edu.
8
Department of Pediatrics/U.S. Department of Agriculture/Agricultural Research Service/Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: loningf@bcm.edu.

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.

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

PMID:
27889186
PMCID:
PMC5695235
DOI:
10.1016/j.ccell.2016.10.007
[Indexed for MEDLINE]
Free PMC Article

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