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.
Yang
Fan
F
Department of Gene Regulation and Drug Discovery, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA.
Huang
Xiongfei
X
Yi
Tangsheng
T
Yen
Yun
Y
Moore
David D
DD
Huang
Wendong
W
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D005260:Female; D018816:Genes, cdc; D006505:Hepatitis / Q000235:genetics / Q000378:metabolism; D007178:Inbreeding; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency* / Q000235:genetics; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics; D015854:Up-Regulation; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated