Fibroblast Growth Factor 19 Activates the Unfolded Protein Response and Mitogen-Activated Protein Kinase Phosphorylation in H-69 Cholangiocyte Cells.

BACKGROUND: Cholangiocytes are injured in many biliary tract diseases that result in cirrhosis, cholangiocarcinoma and need for liver transplantation. Recent studies demonstrate that the hormone Fibroblast Growth Factor 19 (FGF19) is produced in the ileum and regulates hepatic gene expression via the enterohepatic circulation. However, the role of FGF19 on cholangiocytes remains largely unknown. The purpose of this study was to elucidate the effect of FGF19 on cholangiocyte gene and protein expression. METHODS: Cultured human cholangiocyte-derived H69 cells were treated with FGF19 (0-50ng/ml) and expression of genes and proteins involved in the Unfolded Protein Response (UPR) and mitogen-activated protein kinase (MAPK) pathways were studied using RT-PCR and Western blot analysis. RESULTS: FGF19-induced gene and protein expression of the UPR genes BiP and CHOP increased in a dose-responsive pattern. The UPR protein P-eIF2a displayed a bimodal pattern of protein expression, with 10ng/ml of FGF19 maximally reducing and 50ng/ml maximally increasing expression. MAPK pathway protein expression (P-JNK, P-ERK, P-38) displayed a similar bimodal pattern of expression with 2.5ng/ml of FGF19 decreasing expression and 25ng/ml of FGF19 increasing expression. CONCLUSIONS: FGF19 treatment of H69 cells selectively activates BiP and CHOP in a dose-dependent manner. FGF19 also regulates P-eIF2a and MAPK protein expression with a bimodal response. We speculate that FGF19 has an important role in the pathogenesis of many human cholangiopathies and cholestatic liver disorders.