Spontaneous Development of Liver Tumors in the Absence of the Bile Acid Receptor Farnesoid X Receptor

Farnesoid X receptor (FXR, NR1H4) is a member of the nuclear hormone receptor superfamily, which plays an essential role in regulating bile acid, lipid, and glucose homeostasis. Both male and female FXR(-/-) mice spontaneously developed liver tumors; however, no other tumors were developed after 15 months of age. In contrast, no liver tumors were observed in wild-type mice of the same age. Histologic analyses confirm that tumors were hepatocellular adenoma and carcinoma. Although there was no obvious tumor at ages 9 to 12 months, FXR(-/-) livers displayed prominent liver injury and inflammation. Strong labeling of apoptotic hepatocytes and liver damage-induced compensatory regeneration were observed. Deregulation of genes involved in bile acid homeostasis in FXR(-/-) mice was consistent with abnormal levels of bile acids presented in serum and liver. Genes involved in inflammation and cell cycle were up-regulated in aging FXR(-/-) mice but not in wild-type controls. Increasing the bile acid levels by feeding mice with a 0.2% cholic acid diet strongly promoted N-nitrosodiethylamine-initiated liver tumorigenesis, whereas lowering bile acid pool in FXR(-/-) mice by a 2% cholestyramine feeding significantly reduced the malignant lesions. Our results suggest an intriguing link between metabolic regulation and hepatocarcinogenesis.