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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

Expression of FGF19 and FGFR4 in liver tissue of patients with PBC.(A) FGF19 mRNA expression was significantly enhanced both in non-cirrhotic (n = 24) and cirrhotic (n = 21) PBC livers. (B) Expression of liver FGF19 mRNA in non-cirrhotic patients increased along with the stage of fibrosis. Levels of mRNA expression were normalized with glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and presented as a fold-change relative to control. Bars indicate the mean ± SEM. In cirrhotic liver (n = 21) protein levels of (C) FGF19 and (D) FGFR4 were substantially increased when compared to control tissue (n = 21). Changes in protein levels were determined by densitometry analyses after normalization to α/β tubulin as a control for loading. Data presented as the box-and-whisker plot with median value (middle line).
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f2: Expression of FGF19 and FGFR4 in liver tissue of patients with PBC.(A) FGF19 mRNA expression was significantly enhanced both in non-cirrhotic (n = 24) and cirrhotic (n = 21) PBC livers. (B) Expression of liver FGF19 mRNA in non-cirrhotic patients increased along with the stage of fibrosis. Levels of mRNA expression were normalized with glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and presented as a fold-change relative to control. Bars indicate the mean ± SEM. In cirrhotic liver (n = 21) protein levels of (C) FGF19 and (D) FGFR4 were substantially increased when compared to control tissue (n = 21). Changes in protein levels were determined by densitometry analyses after normalization to α/β tubulin as a control for loading. Data presented as the box-and-whisker plot with median value (middle line).

Mentions: In non-cirrhotic PBC livers FGF19 mRNA expression was significantly increased in comparison to controls (9 fold; p = 0.01, Fig. 2A) and was associated with fibrosis stage at liver biopsy (Fig. 2B). FGF19 mRNA showed a positive correlation with cholestatic parameters (ALP: Rho = 0.469, p = 0.03; bilirubin: Rho = 0.561, p = 0.007) and Mayo Risk Score for PBC (r = 0.610, p = 0.002). In non-cirrhotic PBC FGF19 mRNA correlated negatively with HRQoL parameters in PBC-27 (Dryness: r = 0.519, p = 0.02) and SF-36 (Bodily Pain: r = −0.531, p = 0.02, General Health: r = −478, p = 0.03 and both Physical and Mental Summary Components: (r = −0.498, p = 0.03 and r = −0.446, p < 0.05 respectively). These data are summarized in Table 3. There was no relationship between FGF19 mRNA and age of the patients or UDCA medication (data not shown).


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)

Expression of FGF19 and FGFR4 in liver tissue of patients with PBC.(A) FGF19 mRNA expression was significantly enhanced both in non-cirrhotic (n = 24) and cirrhotic (n = 21) PBC livers. (B) Expression of liver FGF19 mRNA in non-cirrhotic patients increased along with the stage of fibrosis. Levels of mRNA expression were normalized with glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and presented as a fold-change relative to control. Bars indicate the mean ± SEM. In cirrhotic liver (n = 21) protein levels of (C) FGF19 and (D) FGFR4 were substantially increased when compared to control tissue (n = 21). Changes in protein levels were determined by densitometry analyses after normalization to α/β tubulin as a control for loading. Data presented as the box-and-whisker plot with median value (middle line).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Expression of FGF19 and FGFR4 in liver tissue of patients with PBC.(A) FGF19 mRNA expression was significantly enhanced both in non-cirrhotic (n = 24) and cirrhotic (n = 21) PBC livers. (B) Expression of liver FGF19 mRNA in non-cirrhotic patients increased along with the stage of fibrosis. Levels of mRNA expression were normalized with glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and presented as a fold-change relative to control. Bars indicate the mean ± SEM. In cirrhotic liver (n = 21) protein levels of (C) FGF19 and (D) FGFR4 were substantially increased when compared to control tissue (n = 21). Changes in protein levels were determined by densitometry analyses after normalization to α/β tubulin as a control for loading. Data presented as the box-and-whisker plot with median value (middle line).
Mentions: In non-cirrhotic PBC livers FGF19 mRNA expression was significantly increased in comparison to controls (9 fold; p = 0.01, Fig. 2A) and was associated with fibrosis stage at liver biopsy (Fig. 2B). FGF19 mRNA showed a positive correlation with cholestatic parameters (ALP: Rho = 0.469, p = 0.03; bilirubin: Rho = 0.561, p = 0.007) and Mayo Risk Score for PBC (r = 0.610, p = 0.002). In non-cirrhotic PBC FGF19 mRNA correlated negatively with HRQoL parameters in PBC-27 (Dryness: r = 0.519, p = 0.02) and SF-36 (Bodily Pain: r = −0.531, p = 0.02, General Health: r = −478, p = 0.03 and both Physical and Mental Summary Components: (r = −0.498, p = 0.03 and r = −0.446, p < 0.05 respectively). These data are summarized in Table 3. There was no relationship between FGF19 mRNA and age of the patients or UDCA medication (data not shown).

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