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.
Highlights
Primary biliary cirrhosis (PBC) is a slowly progressive autoimmune condition of unknown etiology, predominately affecting middle-aged women[1]
Glycine species of chenodeoxycholic acid (CDCA), glycine and taurine conjugate of ursodeoxycholic acid (UDCA) and 3-O-glucuronide of lithocholic acid (LCA) were independent variables related to serum FGF-19 levels (p < 0.0001)
We demonstrated that expression of fibroblast growth factor 19 (FGF19) is strongly induced in livers of patients with primary biliary cirrhosis (PBC) as both mRNA and protein levels of FGF19 were remarkably increased in cholestatic livers
Summary
Primary biliary cirrhosis (PBC) is a slowly progressive autoimmune condition of unknown etiology, predominately affecting middle-aged women[1]. We analyzed the expression of FGF19 and other genes involved in the regulation of bile acids synthesis in livers of patients with PBC in order to determine whether the FGF19 signaling pathway is activated in PBC. These phenomena are of potential clinical relevance in view of the recent interest in both FXR and FGF19 agonists as potential therapeutic modalities in chronic liver diseases. In order to get more insight in these important processes we evaluated FGF19 concentration in the serum of PBC patients and searched for their potential relationships with vital clinical and laboratory findings
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