Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice

Insook Kim

Keiichirou Morimura

Yatrik Shah

Qian Yang

Jerrold Ward

Frank Gonzalez

Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda Maryland, 20892

Correspondence: Frank J. Gonzalez. Building 37, Room 3106, Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda Maryland, 20892. Email: vog.hin.xileh@znogjf; Phone: 301-496-9067; Fax: 301-496-8409

Abstract

The farnesoid X receptor (FXR) controls the synthesis and transport of bile acids. Mice lacking expression of FXR, designated Fxr-null, have elevated levels of serum and hepatic bile acids and an increase in bile acid 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 are rarely observed in mice. At 3-months, Fxr-null mice had increased expression of the proinflammatory cytokine IL-1β mRNA and elevated β-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 bile acids in hepatocarcinogenesis.

Keywords: farnesoid X receptor, c-Myc, Il-1β, β-catenin, PCNA, bromodeoxyuridine

Abstract

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