Circadian Homeostasis of Liver Metabolism Suppresses Hepatocarcinogenesis

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

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.

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / metabolism
  • Circadian Clocks*
  • Disease Models, Animal
  • Gene Expression Regulation
  • Genetic Predisposition to Disease
  • Homeostasis
  • Humans
  • Liver / metabolism
  • Liver Cirrhosis / genetics*
  • Liver Cirrhosis / metabolism
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Metabolome
  • Mice
  • Non-alcoholic Fatty Liver Disease / complications
  • Non-alcoholic Fatty Liver Disease / genetics*
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*

Substances

  • Receptors, Cytoplasmic and Nuclear
  • farnesoid X-activated receptor
  • constitutive androstane receptor