Journal
HEPATOLOGY COMMUNICATIONS
Volume 2, Issue 12, Pages 1567-1582Publisher
JOHN WILEY & SONS LTD
DOI: 10.1002/hep4.1263
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Funding
- National Cancer Institute Intramural Research Program, Center for Cancer Research, National Institutes of Health (NIH) [U54 ES16015]
- NIH [R01DK098336, 1R01AG049493]
- Japanese Society for the Promotion of Science
- Japanese Society for the Promotion of Sciences, Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers [S2601]
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Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths worldwide, and an association between altered bile acid (BA) metabolism, down-regulation of farnesoid X receptor (FXR), which is a master regulator of BA metabolism, and hepatocarcinogenesis has been documented. While global FXR deficiency in mice results in spontaneous HCC with aging, the contribution of tissue-specific FXR deficiency to hepatocarcinogenesis remains unclear. In this study, the prevalence of hepatic tumors, expression of genes related to tumorigenesis, and serum/liver BA levels were compared among male whole-body Fxr-null, hepatocyte-specific Fxr-null (Fxr(Delta Hep)), and enterocyte-specific Fxr-null (Fxr(Delta Hep) ) mice at the age of 3, 14, and 20 months. More than 90% of 20-month-old whole-body Fxr-null mice had hepatic tumors with enhanced hepatic expression of myelocytomatosis oncogene (Myc) and cyclin-dependent kinase 4 (Cdk4) messenger RNAs (mRNAs) and elevated serum taurocholate (TCA) and tauromuricholate (TMCA) and their respective unconjugated derivatives. The incidence of hepatic tumors was significantly lower in Fxr(Delta Hep) and Fxr(Delta IE) mice (20% and 5%, respectively), and the increases in Myc and Cdk4 mRNA or serum BA concentrations were not detected in these mice compared to FXr(floxed)([fl]/fl) mice; a similar tendency was observed in 14-month-old mice. However, increased hepatic c-Myc protein expression was found only in Fxr-null mice at the age of 3, 14, and 20 months. Treatment with TCA induced Myc expression in Fxr-null cultured primary mouse hepatocytes but not in wild-type (WT) mouse hepatocytes, demonstrating that the combination of hepatocyte FXR disruption with elevated TCA is required for Myc induction and ensuing age-dependent hepatocarcinogenesis in Fxr-null mice. Conclusion: There is a relatively low risk of hepatic tumors by inhibition of FXR in enterocytes, likely due to the lack of increased TCA and Myc induction.
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