title: Selective Regulation of FGF19 and FGF21 Expression by Cellular and Nutritional Stress.
abstract: Fibroblast growth factor 19 (FGF19) and FGF21 are members of a subfamily of the FGFs called endocrine FGFs. FGF19 regulates the bile acid synthetic pathway. FGF19 expression is induced by farnesoid X receptor (FXR), a nuclear hormone receptor activated by bile acids in the small intestine. FGF21 plays an important role in lipolysis that occurs in white adipose tissue. FGF21 expression is stimulated by the nuclear fatty acid receptor peroxisome proliferator-activated receptor α (PPARα) in the liver. FGF19 and FGF21 were recently identified as targets of activating transcription factor 4 (ATF4), which is activated in response to endoplasmic reticulum (ER) stress. ATF4 is also activated by oxidative stress and amino acid deprivation. In this study, we investigated FGF19 and FGF21 expression in response to oxidative stress and amino acid deprivation. We found that FGF19 mRNA is induced by oxidative stress inducers in Caco-2 cells, which are derived from the human intestinal epithelium, and rat intestinal epithelial IEC6 cells. In contrast, ileal FGF15 expression, the rodent ortholog of human FGF19, is not increased by oxidative stress. No notable changes in expression of FGF15/19 took place under amino acid deprivation either in vitro or in vivo. In contrast, FGF21 expression is induced by oxidative stress and amino acid deprivation both in vitro and in vivo. These results indicate distinctive patterns of regulation of FGF19 expression by ER stress, and FGF21 expression by ER stress, oxidative stress, and amino acid deprivation through ATF4 activation.
authors.affiliation: Department of Applied Biological Chemistry, The University of Tokyo.
authors.forename: Makoto
authors.initials: M
authors.lastname: Shimizu
authors.forename: Hitomi
authors.initials: H
authors.lastname: Morimoto
authors.forename: Ryuto
authors.initials: R
authors.lastname: Maruyama
authors.forename: Jun
authors.initials: J
authors.lastname: Inoue
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Sato
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000596:Amino Acids / Q000172:deficiency*; D000818:Animals; D018938:Caco-2 Cells; D002460:Cell Line; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009752:Nutritional Status; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction
chemical_list: D000596:Amino Acids; C497110:Atf4 protein, rat; C117476:FGF19 protein, human; D012333:RNA, Messenger; C414620:fibroblast growth factor 21; D051701:Activating Transcription Factor 4; D005346:Fibroblast Growth Factors