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. 2007 May;28(5):940-6.
doi: 10.1093/carcin/bgl249. Epub 2006 Dec 20.

Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice

Insook Kim  1 , Keiichirou Morimura, Yatrik Shah, Qian Yang, Jerrold M Ward, Frank J Gonzalez
Affiliations

Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice

Insook Kim et al. Carcinogenesis. 2007 May.

Abstract

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.

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Figures

Figure 1
Figure 1
Gene expression analysis from liver tissue in 3-month-old (3mo) and 12-month-old (12mo) wild-type and Fxr-null mice. FXR, CYP7A1, and SHP mRNA expression was assessed by qPCR. Expression was normalized to β-actin and each bar represents the mean value ± S.D. (*)= p < 0.05 compared to livers from age-matched wild-type controls.
Figure 2
Figure 2
Body weights, liver weights and bile acid levels in wild-type and Fxr-null mice. Body weights and liver weights were determined in 3-month-old and 12-month-old wild-type (WT) and Fxr-null mice. Serum and bile acid pool size determined in 3-month-old (3mo) and serum and liver bile acids determined 12-month-old (12mo) wild-type (WT) and Fxr-null mice. (*)= p < 0.05
Figure 3
Figure 3
Representative photomicrographs of liver lesions from 12 month-old Fxr-null mice. (a) Representative Fxr-null liver with macroscopic gross lesion. (b) Toxic lesions including hypertrophic and eosinophilic hepatocytes accompanied by fat disposition, were detected in most Fxr-null mouse livers to various extents. Altered cell foci (arrows) were detected at a high incidence in this group regardless of the gender (original magnification X100). (c) Representative photomicrograph of a hepatocellular adenoma (arrow) which was characterized as well-circumscribed lesions composed of well-differentiated hepatocytes, compressing adjacent parenchyma without normal lobular architecture (original magnification X100). (d) Photomicrograph of hepatocellulr carcinoma (original magnification X400) (e) Photomicrograph of mixed tumor (original magnification X100). Histologically, this tumor consisted of hepatocellular (left side) and cholangiocellular (right side) components, and involved increased fibrous stroma detected by Masson’s Trichrome staining (f; original magnification X40). The hepatocellular component showed a trabecular growth pattern and consisted of moderately differentiated neoplastic hepatocytes, and cholangiocellular components showed poorly formed tubular structures lined by low cuboidal cells. Based on these findings, this mixed tumor was diagnosed as a hepatocholangiocellular carcinoma. (g) Oval cell proliferation (arrows) and ductules (original magnification X200). (h) Mixed tumor with inflammatory cell infiltration, ductules formation, and fibrosis (original magnification X200)
Figure 4
Figure 4
(A) Gene expression analysis from liver tissue in 3-month-old (3mo) and 12-month-old (12mo) wild-type and Fxr-null mice. IL-1β, C-Myc, β-catenin and PCNA mRNA expression was assessed by qPCR. Expression was normalized to β-actin and each bar represents the mean value ± S.D. (*)= p < 0.05 compared to livers from age-matched wild-type controls. (B) Western blot analysis of c-myc and β-catenin was performed using total protein extract from livers without macroscopic gross lesions. GAPDH was used as an equal loading control. Bars at the right side indicate positions of size markers (Bio-rad Pre-stained SDS-PAGE standard low range).
Figure 5
Figure 5
Induction of hepatocyte proliferation and increase in hepatocyte Tunel index in Fxr-null mice. (A) Immunohistochemistry of BrdU-labeled hepatocyte nuclei from livers of 3-month-old (3mo) and 12-month-old (12mo) wild-type (WT) and Fxr-null mice. (B) Quantitation of BrdU labeling index from livers of 3-month-old (3mo) and 12-month-old (12mo) wild-type (WT) and Fxr-null mice. (C) Immunohistochemistry of Tunel positive hepatocyte nuclei from livers of 3-month-old (3mo) and 12-month-old (12mo) wild-type (WT) and Fxr-null mice. (D) Quantitation of hepatocyte Tunel index from livers of 3-month-old (3mo) and 12-month-old (12mo) wild-type (WT) and Fxr-null mice. Quantitation was done by counting at least 10 randomly chosen fields (X200) from three mice livers. Each bar represents the mean value ± S.D. (*)= p < 0.05 compared to livers from age-matched wild-type controls.
Figure 6
Figure 6
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