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Expression of hepatic Fibroblast Growth Factor 19 is enhanced in Primary Biliary Cirrhosis and correlates with severity of the disease.

Wunsch E, Milkiewicz M, Wasik U, Trottier J, Kempińska-Podhorodecka A, Elias E, Barbier O, Milkiewicz P - Sci Rep (2015)

Bottom Line: Protein levels of FGF19, FGF receptor 4, FXR and short heterodimer partner were increased in cirrhotic livers (9-fold, p < 0.001; 3.5-fold,p = 0.007; 2.4-fold,p < 0.0001; 2.8-fold,p < 0.0001 vs controls, respectively) which was accompanied by down-regulation of CYP7A1 (50% reduction, p = 0.006).We conclude that PBC induces characteristic changes in liver expression of BAs synthesis regulatory molecules.FGF19 correlates with severity of liver disease and can potentially serve as an indicator of chronic cholestatic liver injury.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical and Molecular Biochemistry, Pomeranian Medical University in Szczecin, Szczecin, Poland.

ABSTRACT
Cholestasis induces adaptive mechanisms protecting the liver against bile acids (BA) toxicity including modulation of BA synthesis. Whether fibroblast growth factor 19 (FGF19) or farnesoid X receptor (FXR) dependent signaling are involved in the regulation of BA homeostasis in primary biliary cirrhosis (PBC) remains unknown. Here we analyzed hepatic expression of FGF19 and other genes relevant to the adaptive response to cholestasis in tissues from non-cirrhotic (n = 24) and cirrhotic (n = 21) patients along with control tissues (n = 21). Moreover we searched for relationships between serum FGF19 and laboratory/clinical findings in 51 patients. Hepatic FGF19 mRNA expression was increased in non-cirrhotic and cirrhotic tissues (9-fold,p = 0.01; 69-fold,p < 0.0001, respectively). Protein levels of FGF19, FGF receptor 4, FXR and short heterodimer partner were increased in cirrhotic livers (9-fold, p < 0.001; 3.5-fold,p = 0.007; 2.4-fold,p < 0.0001; 2.8-fold,p < 0.0001 vs controls, respectively) which was accompanied by down-regulation of CYP7A1 (50% reduction, p = 0.006). Serum and liver levels of FGF19 correlated with worse liver biochemistry, BAs, quality of life and Mayo Risk Score. Serum FGF19 was elevated in UDCA non-responders. We conclude that PBC induces characteristic changes in liver expression of BAs synthesis regulatory molecules. FGF19 correlates with severity of liver disease and can potentially serve as an indicator of chronic cholestatic liver injury.

No MeSH data available.


Related in: MedlinePlus

The hepatic expression of FGF19 and FGFR4 protein in cirrhotic patients with PBC and controls.Representative light micrographs of hematoxylin stained liver sections of control (A) and PBC (F). Immunofluorescence staining of liver tissue showed that in comparison to controls (B,C) expression of both (G) FGF19 (red) and (H) FGFR4 (green) were substantively increased in PBC. Nuclei (blue) stained with DAPI (D,I). Merged immunofluorescent images of FGF19, FGFR4 and DAPI (E,J) demonstrated that in chronic cholestatic PBC livers FGF19 produced by hepatocytes binds to the FGFR4 (J).
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f3: The hepatic expression of FGF19 and FGFR4 protein in cirrhotic patients with PBC and controls.Representative light micrographs of hematoxylin stained liver sections of control (A) and PBC (F). Immunofluorescence staining of liver tissue showed that in comparison to controls (B,C) expression of both (G) FGF19 (red) and (H) FGFR4 (green) were substantively increased in PBC. Nuclei (blue) stained with DAPI (D,I). Merged immunofluorescent images of FGF19, FGFR4 and DAPI (E,J) demonstrated that in chronic cholestatic PBC livers FGF19 produced by hepatocytes binds to the FGFR4 (J).

Mentions: In PBC cirrhotic livers FGF19 expression was significantly increased in comparison to controls both at mRNA (69-fold, p < 0.0001, Fig. 2A) and protein levels (9-fold, p < 0.0001, Fig. 2C) which was accompanied by enhanced expression of FGFR4 protein (3.5 fold, p = 0.007, Fig. 2D). Immunohistological analyses depicted a clear difference in hepatic expression of FGF19 and FGFR4 protein between patients with PBC and controls (Fig. 3). Co-localization of the imunostainings demonstrated that FGF19 produced by hepatocytes binds to the FGFR4, which may confirm autocrine/paracrine manner of FGF19 action.


Expression of hepatic Fibroblast Growth Factor 19 is enhanced in Primary Biliary Cirrhosis and correlates with severity of the disease.

Wunsch E, Milkiewicz M, Wasik U, Trottier J, Kempińska-Podhorodecka A, Elias E, Barbier O, Milkiewicz P - Sci Rep (2015)

The hepatic expression of FGF19 and FGFR4 protein in cirrhotic patients with PBC and controls.Representative light micrographs of hematoxylin stained liver sections of control (A) and PBC (F). Immunofluorescence staining of liver tissue showed that in comparison to controls (B,C) expression of both (G) FGF19 (red) and (H) FGFR4 (green) were substantively increased in PBC. Nuclei (blue) stained with DAPI (D,I). Merged immunofluorescent images of FGF19, FGFR4 and DAPI (E,J) demonstrated that in chronic cholestatic PBC livers FGF19 produced by hepatocytes binds to the FGFR4 (J).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4544021&req=5

f3: The hepatic expression of FGF19 and FGFR4 protein in cirrhotic patients with PBC and controls.Representative light micrographs of hematoxylin stained liver sections of control (A) and PBC (F). Immunofluorescence staining of liver tissue showed that in comparison to controls (B,C) expression of both (G) FGF19 (red) and (H) FGFR4 (green) were substantively increased in PBC. Nuclei (blue) stained with DAPI (D,I). Merged immunofluorescent images of FGF19, FGFR4 and DAPI (E,J) demonstrated that in chronic cholestatic PBC livers FGF19 produced by hepatocytes binds to the FGFR4 (J).
Mentions: In PBC cirrhotic livers FGF19 expression was significantly increased in comparison to controls both at mRNA (69-fold, p < 0.0001, Fig. 2A) and protein levels (9-fold, p < 0.0001, Fig. 2C) which was accompanied by enhanced expression of FGFR4 protein (3.5 fold, p = 0.007, Fig. 2D). Immunohistological analyses depicted a clear difference in hepatic expression of FGF19 and FGFR4 protein between patients with PBC and controls (Fig. 3). Co-localization of the imunostainings demonstrated that FGF19 produced by hepatocytes binds to the FGFR4, which may confirm autocrine/paracrine manner of FGF19 action.

Bottom Line: Protein levels of FGF19, FGF receptor 4, FXR and short heterodimer partner were increased in cirrhotic livers (9-fold, p < 0.001; 3.5-fold,p = 0.007; 2.4-fold,p < 0.0001; 2.8-fold,p < 0.0001 vs controls, respectively) which was accompanied by down-regulation of CYP7A1 (50% reduction, p = 0.006).We conclude that PBC induces characteristic changes in liver expression of BAs synthesis regulatory molecules.FGF19 correlates with severity of liver disease and can potentially serve as an indicator of chronic cholestatic liver injury.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical and Molecular Biochemistry, Pomeranian Medical University in Szczecin, Szczecin, Poland.

ABSTRACT
Cholestasis induces adaptive mechanisms protecting the liver against bile acids (BA) toxicity including modulation of BA synthesis. Whether fibroblast growth factor 19 (FGF19) or farnesoid X receptor (FXR) dependent signaling are involved in the regulation of BA homeostasis in primary biliary cirrhosis (PBC) remains unknown. Here we analyzed hepatic expression of FGF19 and other genes relevant to the adaptive response to cholestasis in tissues from non-cirrhotic (n = 24) and cirrhotic (n = 21) patients along with control tissues (n = 21). Moreover we searched for relationships between serum FGF19 and laboratory/clinical findings in 51 patients. Hepatic FGF19 mRNA expression was increased in non-cirrhotic and cirrhotic tissues (9-fold,p = 0.01; 69-fold,p < 0.0001, respectively). Protein levels of FGF19, FGF receptor 4, FXR and short heterodimer partner were increased in cirrhotic livers (9-fold, p < 0.001; 3.5-fold,p = 0.007; 2.4-fold,p < 0.0001; 2.8-fold,p < 0.0001 vs controls, respectively) which was accompanied by down-regulation of CYP7A1 (50% reduction, p = 0.006). Serum and liver levels of FGF19 correlated with worse liver biochemistry, BAs, quality of life and Mayo Risk Score. Serum FGF19 was elevated in UDCA non-responders. We conclude that PBC induces characteristic changes in liver expression of BAs synthesis regulatory molecules. FGF19 correlates with severity of liver disease and can potentially serve as an indicator of chronic cholestatic liver injury.

No MeSH data available.


Related in: MedlinePlus