In:
Molecular Endocrinology, The Endocrine Society, Vol. 26, No. 5 ( 2012-05-01), p. 775-785
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.
Type of Medium:
Online Resource
ISSN:
0888-8809
,
1944-9917
DOI:
10.1210/me.2011-1383
Language:
English
Publisher:
The Endocrine Society
Publication Date:
2012
detail.hit.zdb_id:
1492112-1