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Circadian Homeostasis of Liver Metabolism Suppresses Hepatocarcinogenesis

2016; Cell Press; Volume: 30; Issue: 6 Linguagem: Inglês

10.1016/j.ccell.2016.10.007

1878-3686

Nicole M. Kettner, Horatio Voicu, Milton J. Finegold, Cristian Coarfa, Arun Sreekumar, Nagireddy Putluri, Chinenye A. Katchy, Choogon Lee, David D. Moore, Loning Fu,

Diet, Metabolism, and Disease

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.