Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor

被引:390
作者
Yang, Fan
Huang, Xiongfei
Yi, Tangsheng
Yen, Yun
Moore, David D.
Huang, Wendong
机构
[1] City Hope Natl Med Ctr, Beckman Res Inst, Dept Gene Regulat & Drug Discovery, Duarte, CA 91010 USA
[2] City Hope Natl Med Ctr, Beckman Res Inst, Dept Clin & Mol Pharmacol, Duarte, CA 91010 USA
[3] Fujian Med Univ, Fujian, Peoples R China
[4] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
关键词
D O I
10.1158/0008-5472.CAN-06-1078
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:863 / 867
页数:5
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