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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 CYP7A1, FXR, SHP, phosphorylated ERK1/2 and phosphorylated c-Jun proteins in liver tissue of cirrhotic patients with PBC and controls.Changes in (A) CYP7A1, (B) FXR and (C) SHP levels were determined by densitometry analyses after normalization to α/β tubulin or β-actin as a control for loading. Data presented as the box-and-whisker plot with median value (middle line). Phosphorylated (D) P-ERK1/2 and (E) P-c-Jun bands were quantified by densitometry and normalized to the density of the total ERK1/2 and c-Jun, respectively. Bars indicate the mean ± SEM.
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f4: Expression of CYP7A1, FXR, SHP, phosphorylated ERK1/2 and phosphorylated c-Jun proteins in liver tissue of cirrhotic patients with PBC and controls.Changes in (A) CYP7A1, (B) FXR and (C) SHP levels were determined by densitometry analyses after normalization to α/β tubulin or β-actin as a control for loading. Data presented as the box-and-whisker plot with median value (middle line). Phosphorylated (D) P-ERK1/2 and (E) P-c-Jun bands were quantified by densitometry and normalized to the density of the total ERK1/2 and c-Jun, respectively. Bars indicate the mean ± SEM.

Mentions: Down-regulation of CYP7A1 under intrahepatic cholestatic conditions was detected (almost 50% reduction, p = 0.006 vs control, Fig. 4A). In order to investigate the signaling pathway involved in the observed downregulation of CYP7A1, we examined the expression of proteins which were reported to modulate the expression of this enzyme. In cirrhotic livers, FXR and SHP protein levels were significantly increased in comparison to controls (2.4 fold, p < 0.0001 and 2.8 fold , p < 0.0001, respectively, Fig. 4B,C). Neither the ratio of P-ERK1/2 to total ERK1/2 (0.73 ± 0.23 vs 0.83 ± 0.3 in controls), nor the ratio of P-c-Jun to total c-Jun was altered (1,32 ± 0,3 vs. 1,35 ± 0,35 in controls Fig. 4D,E).


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 CYP7A1, FXR, SHP, phosphorylated ERK1/2 and phosphorylated c-Jun proteins in liver tissue of cirrhotic patients with PBC and controls.Changes in (A) CYP7A1, (B) FXR and (C) SHP levels were determined by densitometry analyses after normalization to α/β tubulin or β-actin as a control for loading. Data presented as the box-and-whisker plot with median value (middle line). Phosphorylated (D) P-ERK1/2 and (E) P-c-Jun bands were quantified by densitometry and normalized to the density of the total ERK1/2 and c-Jun, respectively. Bars indicate the mean ± SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Expression of CYP7A1, FXR, SHP, phosphorylated ERK1/2 and phosphorylated c-Jun proteins in liver tissue of cirrhotic patients with PBC and controls.Changes in (A) CYP7A1, (B) FXR and (C) SHP levels were determined by densitometry analyses after normalization to α/β tubulin or β-actin as a control for loading. Data presented as the box-and-whisker plot with median value (middle line). Phosphorylated (D) P-ERK1/2 and (E) P-c-Jun bands were quantified by densitometry and normalized to the density of the total ERK1/2 and c-Jun, respectively. Bars indicate the mean ± SEM.
Mentions: Down-regulation of CYP7A1 under intrahepatic cholestatic conditions was detected (almost 50% reduction, p = 0.006 vs control, Fig. 4A). In order to investigate the signaling pathway involved in the observed downregulation of CYP7A1, we examined the expression of proteins which were reported to modulate the expression of this enzyme. In cirrhotic livers, FXR and SHP protein levels were significantly increased in comparison to controls (2.4 fold, p < 0.0001 and 2.8 fold , p < 0.0001, respectively, Fig. 4B,C). Neither the ratio of P-ERK1/2 to total ERK1/2 (0.73 ± 0.23 vs 0.83 ± 0.3 in controls), nor the ratio of P-c-Jun to total c-Jun was altered (1,32 ± 0,3 vs. 1,35 ± 0,35 in controls Fig. 4D,E).

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