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

Maruyama, Ryuto; Shimizu, Makoto; Li, Juan; Inoue, Jun; Sato, Ryuichiro

doi:10.1080/09168451.2015.1135045

Cited by 39 publications

(30 citation statements)

References 23 publications

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“…This loop bypasses the negative feedback of glucocorticoids in the hypothalamic-pituitary-adrenal axis in order to sustain gluconeogenesis in liver during starvation [54]. Recently, it has been reported that FGF21 expression is regulated by activating transcription factor 4 (ATF4), a transcription factor activated by various stimuli such as endoplasmic reticulum (ER) stress [55]. ATF4 binds to the amino acid response element (AARE), a binding site for ATF4, in the promoter region of the target genes.…”

Section: Interventions That Modulates Fgf21 Synthesis and Secretionmentioning

confidence: 99%

“…ATF4 binds to the amino acid response element (AARE), a binding site for ATF4, in the promoter region of the target genes. The two response elements for ATF4 (AARE1 and AARE2) have been reported in the promoter region of FGF21 gene [55].…”

Section: Interventions That Modulates Fgf21 Synthesis and Secretionmentioning

confidence: 99%

“…In fact, recent reports suggested that reduced protein intake was an important regulator of liver FGF21 production [66]. FGF21 promoter has amino-acid response elements (AAREs) inducing its expression [55,67,68]. After amino acid deprivation the general control non-derepressible 2 (GCN2)-eukaryotic initiation factor 2 (eIF2) α pathway is activated inducing binding of activating transcription factor 4 (ATF4) and the transcriptional coactivator protein of PPAR-γ PGC-1 α [45,67,68].…”

Section: Proteinsmentioning

confidence: 99%

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Modulation of energy balance by fibroblast growth factor 21

Cuevas‐Ramos

Aguilar-Salinas

2016

Hormone Molecular Biology and Clinical Investigation

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Fibroblast growth factors (FGFs) are a superfamily of 22 proteins related to cell proliferation and tissue repair after injury. A subgroup of three proteins, FGF19, FGF21, and FGF23, are major endocrine mediators. These three FGFs have low affinity to heparin sulfate during receptor binding; in contrast they have a strong interaction with the cofactor Klotho/β-Klotho. FGF21 has received particular attention because of its key role in carbohydrate, lipids, and energy balance regulation. FGF21 improves glucose and lipids metabolism as well as increasing energy expenditure in animal models and humans. Conditions that induce human physical stress such as exercise, lactation, obesity, insulin resistance, and type 2 diabetes influence FGF21 circulating levels. FGF21 also has an anti-oxidant function in human metabolic diseases which contribute to understanding the FGF21 compensatory increment in obesity, the metabolic syndrome, and type 2 diabetes. Interestingly, energy expenditure and weight loss is induced by FGF21. The mechanism involved is through "browning" of white adipose tissue, increasing brown adipose tissue activity and heat production. Therefore, clinical evaluation of therapeutic action of exogenous FGF21 administration is warranted, particularly to treat diabetes and obesity.

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Section: Interventions That Modulates Fgf21 Synthesis and Secretionmentioning

confidence: 99%

Section: Interventions That Modulates Fgf21 Synthesis and Secretionmentioning

confidence: 99%

Section: Proteinsmentioning

confidence: 99%

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Modulation of energy balance by fibroblast growth factor 21

Cuevas‐Ramos

Aguilar-Salinas

2016

Hormone Molecular Biology and Clinical Investigation

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“…It has been reported that FGF21 gene expression is directly regulated by ATF4 (7,8,12,22) and potentially XBP-1 (9). A previous study reported that FGF21 repressed ER stress by inhibiting phosphorylation of eIF2a, an upstream activating factor of ATF4 (9).…”

Section: Discussionmentioning

confidence: 98%

“…Recent studies revealed that expression of FGF21 is induced in response to ER stress and amino acid deprivation via activation of ATF4 (6)(7)(8)(9)(10)(11). The promoter region of FGF21 contains three response elements for ATF4, suggesting FGF21 is a direct target of ATF4 (12).…”

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confidence: 99%

FGF21 Alleviates Hepatic Endoplasmic Reticulum Stress under Physiological Conditions

Maruyama

Shimizu

Hashidume

et al. 2018

Journal of Nutritional Science and Vitaminology

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Summary Fibroblast growth factor 21 (FGF21), mainly synthesized and secreted from the liver, is an endocrine FGF that regulates glucose and fatty acid metabolism to maintain whole body energy homeostasis. Gene expression of FGF21 was previously reported to be induced by endoplasmic reticulum (ER) stress through activating transcription factor 4 (ATF4). It has been reported that drug-induced ER stress is reduced by overexpression of FGF21. However, the function of endogenous FGF21 under physiological conditions such as the postprandial state remains unknown. Here, we examined the effects of both endogenous and exogenous FGF21 on postprandial hepatic ER stress. In mice, postprandial and tunicamycin-induced ER stress was significantly reduced by overexpression of FGF21 using a recombinant adenovirus. FGF21-deficient mice exhibited a more considerable increase in drug-induced ER stress target gene expression than wild-type mice. Following refeeding after fasting, FGF21 deficiency caused severe ER stress in the liver. The postprandial ER stress response was significantly reduced when hepatic FGF21 gene expression was increased by feeding a diet containing the soy protein b-conglycinin which activates ATF4. Together, these results demonstrate that FGF21 reduces the increased expression of a subset of genes in the liver in response to ER stress and may correct metabolic disorders caused by ER stress. Key Words FGF21, ER stress, ATF4, b-conglycinin Fibroblast growth factor 21 (FGF21), a member of the endocrine FGF subfamily (also known as the FGF19 subfamily), is mainly produced by the liver. FGF21 is secreted into the blood circulation, after which it acts on target tissues through a cell-surface FGF receptor (FGFR) together with its coregulator, bKlotho (1). In adipose tissues, FGF21 induces lipolysis and glucose uptake by activation of hormone sensitive lipase and glucose transporter 4, respectively (2, 3). Some hepatic energy metabolic pathways, including ketogenesis and gluconeogenesis, are also regulated by FGF21 in response to fasting. Expression of FGF21 is transcriptionally regulated during fasting via peroxisome proliferator-activated receptor a (PPARa), a nuclear hormone receptor (2, 4). More importantly, several studies revealed that FGF21 improves whole-body insulin sensitivity, inhibits high-fat diet-induced body weight gain and reduces fatty liver disease. Thus, FGF21 is an attractive target molecule for the prevention of metabolic diseases.Endoplasmic reticulum (ER) stress is triggered by excess accumulation of either unfolded or misfolded proteins in the ER, which in turn activates three ER membrane proteins: activating transcription factor 6a (ATF6a), inositol-requiring enzyme 1 (IRE1), and protein kinase RNA-like ER kinase (PERK). During ER stress, activation of PERK results in the phosphorylation of eukaryotic initiation factor 2a (eIF2a) and translational activation of activating transcription factor 4 (ATF4). Subsequently, ATF4 induces a series of target genes involved in amino acid metabolism, red...

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