Role of Farnesoid X Receptor and Bile Acids in Hepatic Tumor Development

Abstract

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 ∆Hep), and enterocyte‐specific Fxr‐null (Fxr ∆IE) 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 ∆Hep and Fxr ∆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.

Farnesoid X Receptor Activation Impairs Liver Progenitor Cell–Mediated Liver Regeneration via the PTEN‐PI3K‐AKT‐mTOR Axis in Zebrafish

“…To determine the molecular mechanism by which FXR activation impairs BEC‐driven liver regeneration, we tested the downstream mediators mostly identified from tumor studies, including PTEN, ( 32 ) SOCS3/STAT3, ( 33 ) Wnt/β‐catenin, ( 34 ) p62/SQSTM1, ( 35 ) p53, ( 36 ) autophagy, ( 37 ) and MYC. ( 38 ) Among these candidates, we identified PTEN as the critical mediator of FXR activation in BEC‐driven liver regeneration. Reducing PTEN phosphatase activity with the PTEN inhibitor SF1670 ( 39 ) in GW4064‐treated regenerating larvae partially, but significantly, rescued the defects in (1) liver size, (2) LPC‐to‐hepatocyte differentiation, and (3) the proliferation and death of BEC‐derived cells (Fig.…”

Oxysterols and Gastrointestinal Cancers Around the Clock

“…Also only 20 and 5% incidence of hepatic tumors was observed in hepatocyte specific and enterocyte specific Fxr knockout mice, respectively. No serum or hepatic increase in bile acid level was observed in either of cell specific knockout models and no change in expression of cell-cycle regulators (88). These results lead to a hypothesis that high bile acid levels and FXR deregulation are needed for HCC development.…”

Diffuse Adenomatosis and Hepatocellular Carcinoma Treated with Liver Transplantation in an Adolescent Female with Kabuki Syndrome with a Novel KMT2D Gene Mutation

“…KMT2D has also been found to be important in the regulation of the hepatic circadian clock and acts as a transcriptional coactivator of PPARƴ2 [16], and the normal rhythmic fluctuation of bile acid levels is eliminated in KMT2D mutant mice [17]. Elevated serum bile acids have been linked in a farnesoid X receptor mouse knock out model with increased expression of the Myc oncogene and hepatic tumor development [18]. Of note, our patient did have elevated serum bile acids; however, they were obtained in a nonfasting state.…”