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

TLDR

Farnesoid X receptor (FXR) is a nuclear hormone receptor that regulates bile acid, lipid, and glucose homeostasis. FXR‑deficient mice spontaneously develop hepatocellular adenomas and carcinomas by 15 months, accompanied by liver injury, inflammation, apoptosis, compensatory regeneration, and deregulation of bile‑acid, inflammatory, and cell‑cycle genes; increasing bile acids accelerates, while reducing them suppresses, tumorigenesis, linking metabolic dysregulation to hepatocarcinogenesis. Cancer Res 2007;67(3):863–867.

Abstract

Abstract 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. [Cancer Res 2007;67(3):863–7]