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

Departments of ¹ Gene Regulation and Drug Discovery and ² Clinical and Molecular Pharmacology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California; ³ Fujian Medical University, Fuzhou, Fujian, China; and ⁴ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas

Requests for reprints: Wendong Huang, Department of Gene Regulation and Drug Discovery, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010. Phone: 626-256-4673, ext. 65203; Fax: 626-256-8704; E-mail: whuang{at}coh.org.

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]

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