title: Circadian Homeostasis of Liver Metabolism Suppresses Hepatocarcinogenesis.
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.
authors.affiliation: 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.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Kettner
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Horatio
authors.initials: H
authors.lastname: Voicu
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Milton J
authors.initials: MJ
authors.lastname: Finegold
authors.affiliation: 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.
authors.forename: Cristian
authors.initials: C
authors.lastname: Coarfa
authors.affiliation: 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.
authors.forename: Arun
authors.initials: A
authors.lastname: Sreekumar
authors.affiliation: 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.
authors.forename: Nagireddy
authors.initials: N
authors.lastname: Putluri
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Chinenye A
authors.initials: CA
authors.lastname: Katchy
authors.affiliation: Program in Neuroscience, Florida State University, College of Medicine, Tallahassee, FL 32306, USA.
authors.forename: Choogon
authors.initials: C
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: David D
authors.initials: DD
authors.lastname: Moore
authors.affiliation: 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.
authors.forename: Loning
authors.initials: L
authors.lastname: Fu
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D057906:Circadian Clocks; D000090702:Constitutive Androstane Receptor; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006706:Homeostasis; D006801:Humans; D008099:Liver / Q000378:metabolism; D008103:Liver Cirrhosis / Q000235:genetics* / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D055442:Metabolome; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000090702:Constitutive Androstane Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated
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