FGF19 (fibroblast growth factor 19) as a novel target gene for activating transcription factor 4 in response to endoplasmic reticulum stress

FGF19 (fibroblast growth factor 19), expressed in the small intestine, acts as an enterohepatic hormone by mediating inhibitory effects on the bile acid synthetic pathway and regulating carbohydrate and lipid metabolism. In an attempt to identify novel agents other than bile acids that induce increased FGF19 expression, we found that some ER (endoplasmic reticulum) stress inducers were effective. When intestinal epithelial Caco-2 cells were incubated with thapsigargin, marked increases were observed in the mRNA and secreted protein levels of FGF19. This was not associated with the farnesoid X receptor. Reporter gene analyses using the 5'-promoter region of FGF19 revealed that a functional AARE (amino-acid-response element) was localized in this region, and this site was responsible for inducing its transcription through ATF4 (activating transcription factor 4), which is activated in response to ER stress. EMSAs (electrophoretic mobility-shift assays) and ChIP (chromatin immunoprecipitation) assays showed that ATF4 bound to this site and enhanced FGF19 expression. Overexpression of ATF4 in Caco-2 cells induced increased FGF19 mRNA expression, whereas shRNA (short hairpin RNA)-mediated depletion of ATF4 significantly attenuated a thapsigargin-induced increase in FGF19 mRNA.