Gender-specific interplay of signaling through β-catenin and CAR in the regulation of xenobiotic-induced hepatocyte proliferation

Toxicol Sci. 2011 Sep;123(1):113-22. doi: 10.1093/toxsci/kfr166. Epub 2011 Jun 24.


Aberrant signaling through the Wnt/β-catenin pathway is a critical determinant in human and rodent liver carcinogenesis and generally accepted to be a potent driver of proliferation. Xenobiotic agonists of the constitutive androstane receptor (CAR) induce massive acute hyperplasia of mouse liver and facilitate the outgrowth of hepatocellular carcinomas with activated β-catenin. In the present study, the interplay of β-catenin-dependent and CAR-dependent signaling in the liver and its effect on hepatocyte proliferation were analyzed in transgenic mice with hepatocyte-specific knockout of Ctnnb1 (encoding β-catenin) following treatment with two CAR agonists, 1,4-bis[2-(3,5-dichloropyridyloxy)]-benzene (TCPOBOP) and phenobarbital. Hepatocyte-specific knockout of β-catenin inhibited CAR agonists-induced hepatocyte proliferation in male mice. By contrast, the proliferative effect of CAR agonists was strongly augmented in female β-catenin knockout animals. This was due to prolonged proliferation of the knockout hepatocytes. CAR-mediated hepatocyte proliferation was, at least in part, dependent on estrogen signaling and was associated with enhanced expression of FoxM1 and elevated activity of the PDK1/p90RSK pathway. In conclusion, our study shows that gender-specific factors determine whether β-catenin signaling plays a pro- or an antiproliferative role in the regulation of mouse hepatocyte proliferation induced by CAR agonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases
  • Animals
  • Cell Proliferation / drug effects
  • Female
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation / drug effects*
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Phenobarbital / toxicity*
  • Protein Array Analysis
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Pyridines / toxicity*
  • Recoverin / agonists
  • Recoverin / genetics*
  • Recoverin / metabolism
  • Ribosomal Protein S6 Kinases, 90-kDa / genetics
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism
  • Sex Factors
  • Wnt Signaling Pathway / drug effects*
  • beta Catenin / genetics*
  • beta Catenin / metabolism


  • Forkhead Box Protein M1
  • Forkhead Transcription Factors
  • Foxm1 protein, mouse
  • Pyridines
  • Rcvrn protein, mouse
  • beta Catenin
  • Recoverin
  • 1,4-bis(2-(3,5-dichloropyridyloxy))benzene
  • 3-Phosphoinositide-Dependent Protein Kinases
  • PDPK1 protein, human
  • Pdpk1 protein, mouse
  • Protein Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Phenobarbital