Selective Regulation of FGF19 and FGF21 Expression by Cellular and Nutritional Stress

Abstract

Summary 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 a (PPARa) 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.

Low‐Protein Diets with Fixed Carbohydrate Content Promote Hyperphagia and Sympathetically Mediated Increase in Energy Expenditure

“…Our findings are in agreement with some reports on lack of liver FGF21 changes with calorie restriction in mice and a reduction in circulating FGF21 with energy restriction in humans . Prior evidence from intestinal‐derived cell lines implicates the existence of amino acid sensing mechanisms in the intestine; whether similar sensing mechanisms occur in vivo remains largely unknown. Here, we uncovered that protein restriction upregulated the transcripts for key intermediaries of amino acid sensing and signaling such as Eif2ak4 (GCN2), Eif2ak3 (PERK), Eif2s1 (eIF2α), Atf2 , Atf4 , Ddit3 (CHOP), and Eif4ebp1 (4EBP1) particularly in the duodenum, with marginal changes in the ileum.…”

Human Postprandial Nutrient Metabolism and Low-Grade Inflammation: A Narrative Review

“…In vitro, mouse colonic epithelial cells which are pre-treated with FGF19 are protected against ROS (H 2 O 2 ) [117]. Conversely, oxidative stress induces FGF19 mRNA expression in vitro, but not in vivo [118]. Furthermore, also in vitro, the activated FGFR4 by FGF19 inhibits Nf-κB signaling [119].…”

Fibroblast growth factor 21 induction by activating transcription factor 4 is regulated through three amino acid response elements in its promoter region

“…1,2) It has been reported that FGF21 ameliorates hepatic steatosis and improves insulin resistance of diabetic mice, making it an attractive drug target of metabolic diseases. 3,4) The expression of FGF21 gene is recently reported to be regulated by endoplasmic reticulum (ER) stress, [5][6][7][8] oxidative stress, 5,9) and amino acid deprivation [9][10][11] through activating transcription factor 4 (ATF4). ER stress is caused by overloading misfolded proteins in ER, and it activates three membrane proteins, activating transcriptional factor 6 (ATF6), inositol requiring 1, and PKR-like endoplasmic reticulum kinase (PERK).…”