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

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.

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Activating transcription factor 4-dependent induction of FGF21 during amino acid deprivation

Biochemical Journal ◽

10.1042/bj20111748 ◽

2012 ◽

Vol 443 (1) ◽

pp. 165-171 ◽

Cited By ~ 131

Author(s):

Ana Luísa De Sousa-Coelho ◽

Pedro F. Marrero ◽

Diego Haro

Keyword(s):

Transcription Factor ◽

Amino Acid ◽

Initiation Factor ◽

Nutrient Deprivation ◽

Fibroblast Growth Factor 21 ◽

Amino Acid Deprivation ◽

Activating Transcription Factor 4 ◽

Activating Transcription Factor ◽

Transcription Factor 4 ◽

Human Fgf21

Nutrient deprivation or starvation frequently correlates with amino acid limitation. Amino acid starvation initiates a signal transduction cascade starting with the activation of the kinase GCN2 (general control non-derepressible 2) phosphorylation of eIF2 (eukaryotic initiation factor 2), global protein synthesis reduction and increased ATF4 (activating transcription factor 4). ATF4 modulates a wide spectrum of genes involved in the adaptation to dietary stress. The hormone FGF21 (fibroblast growth factor 21) is induced during fasting in liver and its expression induces a metabolic state that mimics long-term fasting. Thus FGF21 is critical for the induction of hepatic fat oxidation, ketogenesis and gluconeogenesis, metabolic processes which are essential for the adaptive metabolic response to starvation. In the present study, we have shown that FGF21 is induced by amino acid deprivation in both mouse liver and cultured HepG2 cells. We have identified the human FGF21 gene as a target gene for ATF4 and we have localized two conserved ATF4-binding sequences in the 5′ regulatory region of the human FGF21 gene, which are responsible for the ATF4-dependent transcriptional activation of this gene. These results add FGF21 gene induction to the transcriptional programme initiated by increased levels of ATF4 and offer a new mechanism for the induction of the FGF21 gene expression under nutrient deprivation.

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Regulation of Vascular Endothelial Growth Factor A by Activating Transcription Factor 4

Circulation Research ◽

10.1161/circresaha.108.186544 ◽

2008 ◽

Vol 103 (9) ◽

Author(s):

Steven F. Abcouwer ◽

C. Nathaniel Roybal

Keyword(s):

Vascular Endothelial Growth Factor ◽

Transcription Factor ◽

Growth Factor ◽

Vascular Endothelial ◽

Activating Transcription Factor 4 ◽

Activating Transcription Factor ◽

Transcription Factor 4 ◽

Endothelial Growth Factor

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Transforming Growth Factor β Suppresses Osteoblast Differentiation via the Vimentin Activating Transcription Factor 4 (ATF4) Axis

Journal of Biological Chemistry ◽

10.1074/jbc.m112.372458 ◽

2012 ◽

Vol 287 (43) ◽

pp. 35975-35984 ◽

Cited By ~ 44

Author(s):

Na Lian ◽

Tonghui Lin ◽

Wenguang Liu ◽

Weiguang Wang ◽

Lingzhen Li ◽

...

Keyword(s):

Transcription Factor ◽

Growth Factor ◽

Osteoblast Differentiation ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Activating Transcription Factor 4 ◽

Activating Transcription Factor ◽

Transcription Factor 4

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Induction of autophagy through the activating transcription factor 4 (ATF4)-dependent amino acid response pathway in maternal skeletal muscle may function as the molecular memory in response to gestational protein restriction to alert offspring to maternal nutrition

British Journal Of Nutrition ◽

10.1017/s0007114515002172 ◽

2015 ◽

Vol 114 (4) ◽

pp. 519-532 ◽

Cited By ~ 8

Author(s):

Huan Wang ◽

Gabriel J. Wilson ◽

Dan Zhou ◽

Stéphane Lezmi ◽

Xiuwen Chen ◽

...

Keyword(s):

Skeletal Muscle ◽

Transcription Factor ◽

Amino Acid ◽

Protein Expression ◽

Mrna Expression ◽

Protein Restriction ◽

Activating Transcription Factor 4 ◽

Activating Transcription Factor ◽

Transcription Factor 4

The aim of the present study was to investigate the mechanistic basis of protein deficiency during pregnancy in mother that is transduced to offspring. To this end, timed-pregnant Sprague–Dawley rats were fed either a control (20 % of energy from protein) or low-protein (LP, 8 % of energy from protein) diet during gestation. Tissues were collected after delivery from rat dams, and skeletal muscle was collected at postnatal day 38 from the offspring. Quantitative RT-PCR and Western blot analyses were performed to determine mRNA and protein levels. Histological analysis was performed to evaluate myofibre size. LP dams gained significantly less weight during pregnancy, developed muscle atrophy, and had significantly lower circulating threonine and histidine levels than control dams. The mRNA expression of the well-known amino acid response (AAR) pathway-related target genes was increased only in the skeletal muscle of LP dams, as well as the protein expression levels of activating transcription factor 4 (ATF4) and phosphorylated eukaryotic translation initiation factor 2α (p-eIF2α). The mRNA expression of autophagy-related genes was significantly increased in the skeletal muscle of LP dams. Moreover, the mRNA expression of genes involved in both AAR and autophagy pathways remained elevated and was memorised in the muscle of LP offspring that consumed a post-weaning control diet. Additionally, the LP diet increased an autophagy marker, microtubule-associated proteins 1A/1B light chain 3B (LC3B) protein expression in the skeletal muscle of rat dams, consistent with the initiation of autophagy. The LP diet further increased ATF4 binding at the predicted regions of AAR and autophagy pathway-related genes. Increased binding of ATF4 unveils the crucial role of ATF4 in the activation of autophagy in response to protein restriction. Our data suggest that molecular changes in maternal muscle are memorised in the offspring long after gestational protein restriction, reinforcing the role of maternal signalling in programming offspring health.

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