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

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 À/À 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 À/À 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 À/À 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 À/À 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 À/À mice by a 2% cholestyramine feeding significantly reduced the malignant lesions. Our results suggest an intriguing link between metabolic regulation and hepatocarcinogenesis.

Gut microbiome development along the colorectal adenoma–carcinoma sequence

“…B. wadsworthia, in particular, utilizes taurine-conjugated bile acids in sulphite reduction, and promotes colitis in genetically susceptible mice (Il10 À / À ) 44 . Bile acids have also been shown to cause DNA damage and promote hepatocellular carcinoma in mice 45,46 . Future research would help elucidate how the known risk factors like diet, obesity and smoking collectively act on the gut microbiome in the development of colorectal carcinoma.…”

Inhibition of leydig tumor growth by farnesoid X receptor activation: The in vitro and in vivo basis for a novel therapeutic strategy

“…Indeed, recent studies have highlighted an oncosuppressive role for FXR in a variety of cancer cell types. [8][9][10][11][12][13][14]17,36 However, direct evidence is missing for the in vivo effects of FXR activation in affecting Leydig carcinogenesis. In our study, we have provided the first evidence that GW4064, a synthetic ligand of FXR, induces Leydig tumor regression by a mechanism that involves both inhibition of cell proliferation and induction of apoptosis.…”

The Bile Acid Sensor Farnesoid X Receptor Is a Modulator of Liver Immunity in a Rodent Model of Acute Hepatitis

“…The homeostatic function of FXR in the liver is highlighted by the demonstration that mice harboring a disrupted FXR (FXR Ϫ/Ϫ ) develop spontaneously an array of hepatocellular abnormalities including adenomas and carcinomas. This pattern associates with an increased liver epithelial cell proliferation and expression of proinflammatory cytokines and oncogenes (40,41).…”