Hepatocarcinogenesis in FXR-/- mice mimics human HCC progression that operates through HNF1α regulation of FXR expression

Nian Liu, Zhipeng Meng, Guiyu Lou, Weiping Zhou, Xiaoqiong Wang, Yunfeng Zhang, Lisheng Zhang, Xiyong Liu, Yun Yen, Lily Lai, Barry M. Forman, Zhonggao Xu, Rongzhen Xu, Wendong Huang

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66 Citations (Scopus)

Abstract

Farnesoid X receptor (FXR) (nuclear receptor subfamily 1, group H, member 4) is a member of nuclear hormone receptor superfamily, which plays essential roles in metabolism of bile acids, lipid, and glucose. We previously showed spontaneously hepatocarcinogenesis in aged FXR-/- mice, but its relevance to human hepatocellular carcinoma (HCC) is unclear. Here, we report a systematical analysis of hepatocarcinogenesis in FXR-/- mice and FXR expression in human liver cancer. In this study, liver tissues obtained from FXR-/- and wild-type mice at different ages were compared by microarray gene profiling, histological staining, chemical analysis, and quantitative real-time PCR. Primary hepatic stellate cells and primary hepatocytes isolated from FXR-/-and wild-type mice were also analyzed and compared. The results showed that the altered genes in FXR-/- livers were mainly related to metabolism, inflammation, and fibrosis, which suggest that hepatocarcinogenesis in FXR-/- mice recapitulated the progression of human liver cancer. Indeed, FXR expression in human HCC was down-regulated compared with normal liver tissues. Furthermore, the proinflammatory cytokines, which were up-regulated in human HCC microenvironment, decreased FXR expression by inhibiting the transactivity of hepatic nuclear factor 1α on FXR gene promoter. Our study thereby demonstrates that the down-regulation of FXR has an important role in human hepatocarcinogenesis and FXR-/- mice provide a unique animal model for HCC study.

Original languageEnglish
Pages (from-to)775-785
Number of pages11
JournalMolecular Endocrinology
Volume26
Issue number5
DOIs
Publication statusPublished - May 1 2012
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Liu, N., Meng, Z., Lou, G., Zhou, W., Wang, X., Zhang, Y., Zhang, L., Liu, X., Yen, Y., Lai, L., Forman, B. M., Xu, Z., Xu, R., & Huang, W. (2012). Hepatocarcinogenesis in FXR-/- mice mimics human HCC progression that operates through HNF1α regulation of FXR expression. Molecular Endocrinology, 26(5), 775-785. https://doi.org/10.1210/me.2011-1383