Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice.
The farnesoid X receptor (FXR) controls the synthesis and transport of bile acids (BAs). Mice lacking expression of FXR, designated Fxr-null, have elevated levels of serum and hepatic BAs and an increase in BA pool size. Surprisingly, at 12 months of age, male and female Fxr-null mice had a high incidence of degenerative hepatic lesions, altered cell foci and liver tumors including hepatocellular adenoma, carcinoma and hepatocholangiocellular carcinoma, the latter of which is rarely observed in mice. At 3 months, Fxr-null mice had increased expression of the proinflammatory cytokine IL-1beta mRNA and elevated beta-catenin and its target gene c-myc. They also had increased cell proliferation as revealed by increased PCNA mRNA and BrdU incorporation. These studies reveal a potential role for FXR and BAs in hepatocarcinogenesis.
Kim
Insook
I
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Morimura
Keiichirou
K
Shah
Yatrik
Y
Yang
Qian
Q
Ward
Jerrold M
JM
Gonzalez
Frank J
FJ
D018248:Adenoma, Liver Cell / Q000235:genetics*; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001692:Biological Transport; D006528:Carcinoma, Hepatocellular / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D018281:Cholangiocarcinoma / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D005260:Female; D015870:Gene Expression; D007249:Inflammation / Q000235:genetics; D053583:Interleukin-1beta / Q000032:analysis; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology; D051176:beta Catenin / Q000235:genetics; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D053583:Interleukin-1beta; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D051176:beta Catenin; D000099150:Receptor, Farnesoid X-Activated