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Hormone Molecular Biology and Clinical Investigation

Editor-in-Chief: Chetrite, Gérard S.

Editorial Board: Alexis, Michael N. / Baniahmad, Aria / Beato, Miguel / Bouillon, Roger / Brodie, Angela / Carruba, Giuseppe / Chen, Shiuan / Cidlowski, John A. / Clarke, Robert / Coelingh Bennink, Herjan J.T. / Darbre, Philippa D. / Drouin, Jacques / Dufau, Maria L. / Edwards, Dean P. / Falany, Charles N. / Fernandez-Perez, Leandro / Ferroud, Clotilde / Feve, Bruno / Flores-Morales, Amilcar / Foster, Michelle T. / Garcia-Segura, Luis M. / Gastaldelli, Amalia / Gee, Julia M.W. / Genazzani, Andrea R. / Greene, Geoffrey L. / Groner, Bernd / Hampl, Richard / Hilakivi-Clarke, Leena / Hubalek, Michael / Iwase, Hirotaka / Jordan, V. Craig / Klocker, Helmut / Kloet, Ronald / Labrie, Fernand / Mendelson, Carole R. / Mück, Alfred O. / Nicola, Alejandro F. / O'Malley, Bert W. / Raynaud, Jean-Pierre / Ruan, Xiangyan / Russo, Jose / Saad, Farid / Sanchez, Edwin R. / Schally, Andrew V. / Schillaci, Roxana / Schindler, Adolf E. / Söderqvist, Gunnar / Speirs, Valerie / Stanczyk, Frank Z. / Starka, Luboslav / Sutter, Thomas R. / Tresguerres, Jesús A. / Wahli, Walter / Wildt, Ludwig / Yang, Kaiping / Yu, Qi


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Volume 30, Issue 1

Issues

The regulation of FGF21 gene expression by metabolic factors and nutrients

Anjeza Erickson
  • Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Régis Moreau
  • Corresponding author
  • Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA, Phone: 402-472-7291, Fax: 402-472-1587
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  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2016-06-10 | DOI: https://doi.org/10.1515/hmbci-2016-0016

Abstract

Fibroblast growth factor 21 (FGF21) gene expression is altered by a wide array of physiological, metabolic, and environmental factors. Among dietary factors, high dextrose, low protein, methionine restriction, short-chain fatty acids (butyric acid and lipoic acid), and all-trans-retinoic acid were repeatedly shown to induce FGF21 expression and circulating levels. These effects are usually more pronounced in liver or isolated hepatocytes than in adipose tissue or isolated fat cells. Although peroxisome proliferator-activated receptor α (PPARα) is a key mediator of hepatic FGF21 expression and function, including the regulation of gluconeogenesis, ketogenesis, torpor, and growth inhibition, there is increasing evidence of PPARα-independent transactivation of the FGF21 gene by dietary molecules. FGF21 expression is believed to follow the circadian rhythm and be placed under the control of first order clock-controlled transcription factors, retinoic acid receptor-related orphan receptors (RORs) and nuclear receptors subfamily 1 group D (REV-ERBs), with FGF21 rhythm being anti-phase to REV-ERBs. Key metabolic hormones such as glucagon, insulin, and thyroid hormone have presumed or clearly demonstrated roles in regulating FGF21 transcription and secretion. The control of the FGF21 gene by glucagon and insulin appears more complex than first anticipated. Some discrepancies are noted and will need continued studies. The complexity in assessing the significance of FGF21 gene expression resides in the difficulty to ascertain (i) when transcription results in local or systemic increase of FGF21 protein; (ii) if FGF21 is among the first or second order genes upregulated by physiological, metabolic, and environmental stimuli, or merely an epiphenomenon; and (iii) whether FGF21 may have some adverse effects alongside beneficial outcomes.

Keywords: butyric acid; curcumin; lipoic acid; methionine; retinoic acid

Introduction

The importance of diet and nutrition in the etiology of a number of diseases affecting morbidity and mortality is well recognized. However, the exact nature of how diet impacts health and disease is complex and not fully understood. Nutrients and dietary molecules alter gene expression, modulate protein and metabolite levels in blood and tissues, modify cellular and metabolic pathways, affect epigenetic phenomena, and modify response to drugs. These nutrient-gene interactions thus influence an individual’s response to the environment – including diet – and to therapy. Nutrients act directly, indirectly, and cooperatively with hormones to influence the rate and extent of transcription. Among nutrients, glucose, fatty acids, sterols, vitamin A, vitamin D, and their metabolites are prominent regulators of gene expression. Chief among hormones, insulin, glucagon, glucocorticoids, and growth and thyroid hormones, are essential regulators of metabolic homeostasis.

Since fibroblast growth factor 21 (FGF21) was discovered nearly two decades ago [1], its physiological and pharmacological effects have been extensively studied whereas, comparatively, the regulation of FGF21 gene expression by diet, nutrients, and dietary bioactive compounds is not well characterized. FGF21 is expressed across several tissues, predominantly in liver and adipocyte tissues, and, to a lower extent, in the pancreas, skeletal muscle, heart, kidneys and testes [13]. Unlike most members of the FGF family, FGF21 lacks the FGF heparin-binding domain, allowing FGF21 to be secreted in the bloodstream and act peripherally as well as centrally [4]. Circulating levels of FGF21 are increased in response to fasting [57], macronutrient diet composition [6, 8], and physiological or environmental stress [9] in individuals with obesity, type 2 diabetes, and non-alcoholic fatty liver disease [10]. The broad range responsiveness of FGF21 expression to metabolic variations suggests that FGF21 contributes to metabolic homeostasis in health and disease. Indeed, the pharmacological administration of recombinant FGF21 resulted in a plethora of metabolic outcomes including the increase of fat utilization and energy expenditure, the promotion of fat browning in white and brown adipose tissue, the improvement of thermogenesis, the stimulation of fatty acid oxidation, the stimulation of peroxisome proliferator-activated receptor α (PPARα) and PPARγ transactivation, glucose tolerance and insulin sensitivity, decreased body weight and lowered cholesterol along with serum and hepatic triglyceride levels [5, 6, 1121]. This review focuses on the nutritional factors and metabolic hormones that modulate FGF21 gene expression in rodents and humans, and discusses the underlying transcriptional mechanisms.

Body of review

Regulation by starvation and overnutrition

Animal studies have shown that FGF21 expression is upregulated by drastically different nutritional states, such as in starvation and overnutrition. In contrast, the FGF21 serum levels of healthy subjects remain stable over the course of a day despite wide interindividual variations (21–5300 pg/mL; mean, 450 pg/mL) [22]. Moreover, serum FGF21 is largely unchanged in humans who fasted for 2 days [22], suggesting that secreted FGF21 remains within the tissue of production and acts locally. It is after 7 days of fasting that serum FGF21 notably increases in human subjects [22, 23]. Plasma FGF21 levels are reportedly higher in the obese, in individuals with type 2 diabetes, and in subjects with non-alcoholic liver disease, which correlate with elevated levels of triacylglycerols in the liver [2429]. Overnutrition and refeeding also upregulate FGF21 gene expression. This response may be induced by dietary carbohydrates as it was shown that carbohydrates induce FGF21 gene expression through the transcription factor carbohydrate response element binding protein (ChREBP).

In the liver and isolated hepatocytes, FGF21 expression is induced by starvation in PPARα-dependent and independent manners [57, 30, 31]. As a transcription factor activated by fatty acids, phosphatidylcholine, oleoylethanolamine, and hypolipidemic fibrate drugs, PPARα binds to PPRE in the 5′-flanking region of the FGF21 gene and induces transcription [5, 7] (Figure 1). Liver FGF21 is also induced by a high-fat low-carbohydrate diet [6], a condition that, similar to starvation, stimulates the breakdown of stored fat, the catabolism of fatty acids, ketogenesis, and gluconeogenesis. The FGF21 gene is also upregulated by fasting signals conveyed by glucagon. The actions of the glucagon receptor on glucose and lipid metabolism and on the regulation of body weight and fat mass are mediated in part by FGF21 [36]. The glucagon/FGF21 axis is further discussed below.

Mapping of the response elements and specific transcription factors documented to interact within the 5′-flanking region of the human, mouse, and rat FGF21 gene. (A) Overall layout of the response elements within the 4600 bp upstream of the transcription start site (TSS). (B) Alignment of human, mouse, and rat FGF21 5′-regulatory sequences shown in red or blue boxes the positions of known transcription factor binding sites. The binding sites were retrieved from the literature and confirmed using MatInspector (Genomatix Software GmbH, Munich, Germany). Segments of the 5′-flanking region that do not harbor any documented transcription binding sites were omitted. The 5′ genomic sequences for human, mouse, and rat FGF21 were retrieved from NCBI [32, 33] and aligned using Clustal Omega [34]. The TSSs were positioned based on the following transcript sequences retrieved from ENSEMBL [35]: ENST00000222157 for hFGF21, ENSMUST00000033099 for mFGF21, and ENSRNOT00000028490 for rFGF21.
Figure 1:

Mapping of the response elements and specific transcription factors documented to interact within the 5′-flanking region of the human, mouse, and rat FGF21 gene.

(A) Overall layout of the response elements within the 4600 bp upstream of the transcription start site (TSS). (B) Alignment of human, mouse, and rat FGF21 5′-regulatory sequences shown in red or blue boxes the positions of known transcription factor binding sites. The binding sites were retrieved from the literature and confirmed using MatInspector (Genomatix Software GmbH, Munich, Germany). Segments of the 5′-flanking region that do not harbor any documented transcription binding sites were omitted. The 5′ genomic sequences for human, mouse, and rat FGF21 were retrieved from NCBI [32, 33] and aligned using Clustal Omega [34]. The TSSs were positioned based on the following transcript sequences retrieved from ENSEMBL [35]: ENST00000222157 for hFGF21, ENSMUST00000033099 for mFGF21, and ENSRNOT00000028490 for rFGF21.

Fat cell FGF21 has been shown to be upregulated during adipocyte differentiation [28] and to stimulate glucose uptake in adipocytes [11, 13]. ChREBP is upregulated during adipocyte differentiation and, thus, may be involved in the induction of FGF21 in these cells [37]. In adipocytes, FGF21 is induced by feeding in a PPARγ-dependent manner [38]. PPARγ agonists, such as the thiazolidinedione drugs, also induce FGF21 gene expression in white adipose tissue and isolated adipocytes [28, 39, 40]. Supporting the mediating role of FGF21 in the therapeutic effects of thiazolidinedione is the observation that FGF21-null mice are refractory to both the beneficial and adverse effects of this family of drugs [17].

There is evidence to indicate that the FGF21 gene is autoregulated by circulating FGF21. The administration of recombinant FGF21 to streptozotocin-treated mice dose-dependently repressed FGF21 gene expression in the liver to a greater extent than streptozotocin alone [41]. In a separate study, FGF21 transcript levels were substantially lowered in the liver following FGF21 administration [42]. These results suggest the presence of a negative feedback by FGF21 directed at its own expression.

Regulation by hormones

Glucagon and insulin

A physiological link was established between hepatic glucagon signaling, 5′ adenosine monophosphate-activated protein kinase (AMPK), PPARα, and the expression of FGF21 in mice lacking the glucagon receptor [43]. In these mice, glucagon failed to induce liver AMPK phosphorylation, PPARα and FGF21 gene expression. A lipid infusion composed of PPARα natural ligands also failed to induce liver AMPK phosphorylation, and PPARα and FGF21 gene expression in glucagon receptor-null mice, suggesting that a functional glucagon signaling is required for the PPARα-mediated upregulation of the FGF21 gene. The use of a glucagon receptor agonist raised hepatic expression and blood levels of FGF21 in wild-type mice [36], supporting the notion that chronic glucagon action is mediated through FGF21 expression. Cyphert et al. [44] found that glucagon stimulates FGF21 secretion via a translational and/or post-translational mechanism mediated by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) axis as well as a PKA-independent mechanism. The latter mechanism involves the cAMP activation of exchange protein directly activated by cAMP (EPAC), a guanine nucleotide exchange factor that activates the small guanosine-5′-phosphatase (GTPase) Ras-proximate-1 (Rap1) [45, 46]. Downstream of cAMP, the glucagon/cAMP signaling pathway implicates AMPK and p38 mitogen-activated protein kinase (MAPK).

The cAMP-stimulated transcription factor cyclic AMP-responsive element-binding protein 3-like protein 3 (CREBH) is upregulated during fasting [47, 48] and possibly by glucagon. Fasting and glucagon increases CREBH acetylation, which is required for the formation of the CREBH-PPARα transcriptional complex [49]. In addition to regulating each other’s transcription in fasted liver [47], CREBH and PPARα synergize to activate FGF21 gene expression through the binding of the CREBH-PPARα complex to a highly conserved CRE-peroxisome proliferator-activated response element (PPRE) site in the FGF21 proximal promoter [50]. Glucocorticoid signaling is involved in the regulation of CREBH [48]. In the fasting state, the adrenal gland secretes glucocorticoids, which contribute to upregulate gluconeogenesis and stimulate hepatic glucose output [51].

Glucagon and insulin synergized in primary rat hepatocytes to induce FGF21 mRNA and FGF21 secretion, whereas glucagon alone in the absence of insulin lowered FGF21 mRNAs [44]. In contrast, Uebanso et al. [52] found that glucagon and insulin function in an opposite manner in rat primary hepatocytes: glucagon induced FGF21 mRNA whereas insulin inhibited gene expression. Insulin, through protein kinase B (Akt), reportedly induced FGF21 expression in cultured skeletal muscle cells [53]. Of note, glucagon has been shown to enhance the action of insulin on Akt in hepatocytes [54]. Hence, although glucagon and insulin have opposite broad effects on metabolism, Cyphert et al. [44] showed that these hormones stimulate FGF21 secretion either alone [53] or in combination [44]. Overall, the regulation of FGF21 mRNA levels by glucagon and insulin appears more complex than first anticipated. Either glucagon or insulin has the potential to upregulate FGF21 gene expression.

Thyroid hormone T3

The intraperitoneal injection of thyroid hormone tri-iodothyronine (T3) in mice has been shown to induce hepatic FGF21 gene expression in a dose-dependent manner [55]. The induction was abolished in PPARα-null mice, suggesting that PPARα mediates the effects of T3. A direct interaction among thyroid hormone receptor β, PPARα, and retinoid X receptor (RXR) in hepatocytes was suggested based on the rapid induction of the FGF21 gene by T3 [55]. A distal PPRE site in the 5′ regulatory region of the FGF21 gene was required for T3 action. T3 did not induce FGF21 mRNA in the white adipose tissue of wild-type mice, indicating that tissue specificity may result from a distinct expression profile of the thyroid hormone receptor subtypes. As abnormal blood lipids can be improved with thyroid hormone receptor β agonists, similarly with recombinant FGF21, FGF21 may be a physiologically relevant mediator of T3’s lipid-ameliorating properties.

Regulation by miRNA

Recent studies have found evidence linking microRNAs (miRNAs) to the regulation of metabolism and metabolic disorders [56]. miRNAs are circulating, small, non-coding RNAs of about 19–23 nucleotides long, which regulate gene expression post-transcriptionally by binding primarily to the 3′-untranslated region (3′UTR) of mRNAs and targeting mRNAs for translational repression and degradation. Blood-circulating miRNAs function as signaling molecules by altering gene expression not only in cells and tissues where they are produced but also in distant organs. Their critical role in gene regulation suggests that miRNAs can be markers of health and disease, and potential therapeutic targets. The discovery of miRNAs able to regulate FGF21 expression and impact the metabolic effects of FGF21 has been of special interest in recent years.

FGF21 is a well-known regulator of pancreatic insulin production. Treatment of diabetic mice and rats with FGF21 increased insulin secretion and content in pancreatic islets, improved glucose clearance, and promoted the survival of islets and insulin-secreting INS-1E pancreatic β-cells against glucolipotoxicity and cytokine-induced apoptosis [57]. A recent study investigated miR-577 as a novel mechanism of improving pancreatic β-cell survival and function in diabetic patients [58], in part because miR-577 was predicted to target FGF21 [59]. Chen et al. [58] observed that the blood of diabetic children contained elevated levels of miR-577. They showed that FGF21 3′UTR was a direct target of miR-577 in mouse embryonic pancreatic β-cells as the suppression of miR-577 with anti-miR-577 increased FGF21 mRNA and protein expression in these β-cells. Additional evidence that miR-577 targets FGF21 was provided when the activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt signaling pathways was blocked by miR-577, and when the glucose-stimulated FGF21-induced production of insulin was repressed by miR-577. Hence, their work points to anti-miR-577 as a means to protect and restore the insulinotropic action of FGF21. There are other predicted targets of miR-577 that belong to the FGF family, including FGF5 and FGF23 [59].

Another miRNA that has been shown to play an important role in metabolic disorders is microRNA-212 (miR-212). miR-212 modulates alcoholic liver disease [60] and cardiac insulin resistance during overnutrition [61]. This miRNA is primarily expressed in the central nervous system and, to a lower extent, in adipose, liver, and many other tissues. Xiao et al. [62] reported on the beneficial effects of miR-212 downregulation through exercise in the prevention of non-alcoholic fatty liver disease (NAFLD). The evidence that miR-212 targets FGF21 derives primarily from the observation that synthetic miR-212 mimics decreased FGF21 expression whereas the miR-212 inhibitor increased FGF21 protein levels and decreased lipid synthesis in HepG2 cells. The silencing of FGF21 increased intracellular lipid droplets in HepG2 cells and hindered the anti-lipogenic effect of the miR-212 inhibitor in these cells. In animals, hepatic miR-212 was increased in mice fed a high-fat diet, and negatively regulated FGF21. Collectively, it was concluded that FGF21 is a target of miR-212 and anti-miR-212 therapeutic approaches could be useful for NAFLD patients [62]. Other predicted targets of miR-212 that belong to the FGF family of proteins include FGF1 [63], FGF2, FGF5, FGF9, FGF11, FGF12, and FGF23 [64].

Regulation by endoplasmic reticulum (ER) stress

The ER plays a prominent role in cellular homeostasis by orchestrating the synthesis, folding, maturation, and distribution of over a third of all proteins in the cell [65, 66]. A plethora of studies have linked ER stress with metabolic disturbances and diseases such as insulin resistance, type 2 diabetes, and obesity [6769]. New evidence has indicated that FGF21 gene expression is induced under conditions causing cellular stress, and the upregulation is mediated by activating transcription factor 4 (ATF4) and CCAAT enhancer binding-protein homologous protein (CHOP) [9, 7074]. For the mechanism, the phosphorylation of the α subunit of the eukaryotic initiation factor (eIF2) by protein kinase R-like endoplasmic reticulum kinase (PERK) prompts ATF4 mRNA to be translated. ATF4 translocates to the nucleus and induces transcription of the unfolded protein response (UPR) target genes. These genes include CHOP, a proapoptotic transcription factor that promotes cell death when stress conditions persist [75]. While conserved ATF4-binding sites are apparent in the FGF21 promoter [70], current evidence indicates an absence of a conserved CHOP binding site in the 5′ flanking region (–1497/+5), therefore suggesting that CHOP stabilizes FGF21 transcripts rather than induces FGF21 gene expression [74]. Alternatively, the inositol-requiring enzyme 1 α (IRE1α)/X-box binding protein 1 (XBP1) branch of the UPR was implicated in FGF21 upregulation by ER stressors tunicamycin and thapsigargin [76]. ER stress response elements (ERSE, 5′-CCATT…N(n)…CCACG) to which XBP1 can bind were identified in the human (–150/–128), mouse (–142/–108), and rat (–319/–285) FGF21 promoters [76]. The upregulation of FGF21 expression by the UPR program is viewed as a countermeasure to ER stress as FGF21 acts subsequently to suppress the eukaryotic initiation factor 2α (eIF2α)/ATF4/CHOP pathway [76].

Regulation by nutrients

Carbohydrates

FGF21 hepatic expression and circulating FGF21 levels are influenced by dietary macronutrients. High-carbohydrate diets have been shown to induce FGF21 expression. Liver FGF21 mRNA levels were upregulated in mice fed a lipogenic high-carbohydrate liquid diet rich in dextrose, but not by a high-fat obesogenic diet, although both diets induced hepatosteatosis [77]. The stimulatory role of dextrose (27.5 mM) on FGF21 gene expression had been shown earlier in isolated rat hepatocytes [78]. Hepatic FGF21 gene expression is induced not only by glucose but also by fructose, sucrose, and to a lesser extent, saccharin (an artificial non-caloric sweetener) when provided ad libitum to mice in the drinking water for 24 h [79]. Glucose, fructose, and sucrose, but not saccharin, raised plasma FGF21 levels in these mice. Similar results were observed in human subjects infused with dextrose to reproduce a state of hyperglycemia [79]. ChREBP was implicated in the upregulation of hepatic FGF21 gene expression in response to sucrose intake in mice. ChREBP binds to the ChoRE site in the human FGF21 promoter [80]. A typical ChoRE comprising two E-boxes separated by a 5-bp space exists in the mouse FGF21 promoter [81]. In humans, the ChoRE comprises two imperfect E-boxes separated by 8 bp at –380 to –366 [80]. A negative feedback loop of liver-derived FGF21 acting centrally in the hypothalamus to repress sweet-seeking behavior and reduce meal size has been proposed [79]. Counteracting the stimulation by sugars, the addition of a soybean oil-based emulsion to a high-carbohydrate dextrose-rich diet led to the suppression of FGF21 gene expression in mouse tissues and a lowering of plasma FGF21 levels [77].

Proteins (low-protein diet, methionine- or leucine-restricted diet)

FGF21 hepatic expression and circulating FGF21 are influenced by the level of dietary protein. Serum FGF21 increases on low-protein diets that typically are high in carbohydrates. Singly restricted amino acids, such as methionine [8285] or leucine [70], have been shown to increase hepatic expression and circulating levels of FGF21. Serum FGF21 also increases in the context of ketogenic diets that are high in fat, very low in carbohydrate, and moderate to low in protein. Since FGF21 is induced by both high and low carbohydrate diets, the view is that FGF21 is not regulated by carbohydrates alone but also by the reduction in protein [86]. Feeding a low-protein (5% casein) isoenergetic diet (vs. 15%–20% casein in the control diet) either short-term (8 h) in rats or longer-term (5–11 days) in mice led to an upregulation of FGF21 gene expression in the liver and an increase of FGF21 levels in plasma [87]. In humans, restricting dietary protein for 28 days caused plasma FGF21 to rise [86]. Mechanistically, the PERK/eIF2α/ATF4 branch of the UPR was implicated in FGF21 upregulation by a low-protein diet [86] and methionine restriction [84]. Dietary methionine restriction resulted in the upregulation of hepatic ATF4 expression. Subsequently, ATF4 bound to cAMP response element (CRE). The 5′ flanking region of human FGF21 has two functional ATF4 binding sites associated with amino acid response elements (AARE) [9, 70]. Disruption of these sites abolished ER stress-mediated induction of FGF21. Since leucine deprivation induces the kinase general control non-derepressible protein 2 (GCN2), the involvement of GCN2 (an upstream regulator of ATF4) in FGF21 expression has been proposed. Evidence shows that hepatic FGF21 mRNA levels are markedly decreased in GCN2-null mice fed a low-protein diet [86]; however, low dietary protein is still capable of FGF21 induction, suggesting that there might be alternative mechanisms independent of GCN2 that link low protein and FGF21 upregulation. These alternative mechanisms include PPARα, which when knocked out in mouse liver elicited low serum FGF21 concentrations and weak FGF21 induction by a low-protein diet [86].

Lipids (high-fat diet, fatty acids, retinoic acid)

High-fat diet and polyunsaturated fatty acids

Hepatic FGF21 gene expression and plasma FGF21 levels were induced in mice fed a corn oil-based high-fat diet compared to control mice fed a high-carbohydrate low-fat diet for 5 or 8 weeks [88]. In this study, mice on the high-fat diet gained more weight, consumed more food, had higher epididymal white adipose fat and blood triacylglycerols than control mice. The sustained feeding of the high-fat diet for 8 weeks led to an upregulation of FGF21 mRNA in the liver and white and brown adipose tissue. In contrast, Hao et al. [77] did not observe a significant change in hepatic FGF21 mRNA levels in mice fed a high-fat vs. low-fat diet for 16 weeks. The apparent inconsistencies suggest that high dietary fat is only one factor implicated in FGF21 upregulation and warrant continued investigation. The upregulation of FGF21 gene expression in the adipose tissue by feeding was consistent with the study of Dutchak et al. [15] that showed a meal-dependent increase in FGF21 mRNA in white adipose tissue 4 h after the initiation of a meal during the dark phase. These results illustrate the upregulation of FGF21 in liver and adipose tissue in the context of overnutrition and obesity. Supplementation of the high-fat diet with long-chain polyunsaturated n-3 fatty acids (PUFA), among which are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), caused a comparatively modest induction of hepatic and adipose FGF21 gene expression above that of mice fed the control high-carbohydrate low-fat diet [88]. Mice fed a PUFA-supplemented high-fat diet gained less weight than mice fed the high-fat diet, and stored less fat in the epididymal pads and interscapular depot. Their blood triacylglycerols were also lower than in mice fed the high-fat diet devoid of PUFA. From these studies, it is concluded that although PUFA ameliorated the lipid profile, the mechanism did not overtly implicate FGF21.

Short-chain fatty acids

Butyric acid is a short-chain fatty acid produced in large quantities by bacterial fermentation of dietary fiber in the large intestine. Many of butyrate’s mechanisms of action implicate the regulation of gene expression since butyric acid has histone deacetylase inhibitor (HDAC) properties. Li et al. [89] showed that butyrate induced FGF21 gene expression in the liver of dietary obese mice and in human hepatocellular carcinoma HepG2 cells. The peritoneal injection of butyrate (500 mg/kg body weight) in mice after an overnight fast induced plasma levels of FGF21 and β-hydroxybutyrate, indicating butyrate-enhanced ketogenesis in mice [89]. Other exogenously supplied short-chain fatty acids, such as β-hydroxybutyrate and hexanoate, did not induce FGF21 mRNA or FGF21 protein levels, suggesting the specific role of butyrate. Functional analysis of the FGF21 gene promoter (–1497/+5) revealed the putative involvement of a bezafibrate-responsive distal PPRE site and HDAC3 in the mechanism of butyrate. The use of small interfering RNA (siRNA) to block HDAC3 enhanced the activity of the promoter, suggesting that butyrate induced FGF21 gene expression through the inhibition of HDAC3, but not because of the short-chain fatty acid structure of butyrate. Li et al. [89] examined the regulatory role of butyrate on FGF21 in mouse epididymal fat and did not observe any effect.

α-Lipoic acid (α-LA) is a naturally occurring enzyme cofactor synthesized from octanoic acid in most prokaryotic and eukaryotic microorganisms as well as plant and animal mitochondria and plant plastids [90, 91]. α-LA can also be absorbed from foods (leafy green vegetables and red meats) and dietary supplements. Animal studies indicated that dietary supplementation of (R)-α-LA induced hepatic FGF21 expression and raised FGF21 blood levels above the levels induced by fasting alone [9294]. Moreover, feeding (R)-α-LA to rats reproduced the metabolic effects of FGF21, including the lowering of liver and blood triacylglycerol concentrations, and the decreased expression of lipogenic genes including acetyl-CoA carboxylase 1 (ACACA), fatty acid synthase (FASN), acyl-CoA desaturase 1 (SCD1), elongation of very long chain fatty acids protein 6 (ELOV6), and glycerol-3-phosphate acyltransferase 1 (GPAM) [9294]. (R)-α-LA (50 μM) stimulated the transcription and secretion of FGF21 from human hepatocellular carcinoma HepG2 cells [31]. A comparable outcome was observed in mouse hepatocyte AML12 cells treated with 1 mM α-LA [95]. In these cells, Bae et al. [95] found that α-LA increased FGF21 promoter activity by upregulating CREBH expression and increasing CREBH binding to the FGF21 promoter. The knockdown of CREBH with siRNA attenuated the α-LA-driven induction of the FGF21 gene and protein expression. In the same study, the peritoneal injection of α-LA (100 mg/kg body weight per day for 7 days) in mice induced hepatic CREBH and FGF21 transcript and protein levels, and raised serum FGF21 levels in the fed and fasted states [95]. In HepG2 cells, α-LA altered the chromatin structure of a distal 5′-flanking 400-bp region (–1524/–1124 bp) of the FGF21 gene [31]. The 400-bp fragment was enriched in the acetylated histone H3, which indicated its transcriptional competency to bind transcriptional factors. In silico analysis of putative transcription factors ranked the testis-specific bHLH-Zip transcription factor (SPZ1) as a lead candidate with three mixed E/G-boxes located at –1524/–1513, –1273/–1283, and –1161/–1151 bp in the 5′-flanking region. Reports have indicated that α-LA stimulates the cAMP/PKA signaling [96] and other protein kinases downstream of cAMP, including ERK1/2 [97, 98] and p38MAPK [99, 100]. As SPZ1 has been shown to act downstream of MAPK [101], the cAMP/p38MAPK/SPZ1 axis may play a central role in the mechanism of α-LA.

α-LA is known to induce Phase II detoxification enzymes in a nuclear factor E2-related factor 2 (Nrf2)-dependent manner by eliciting Nrf2 nuclear translocation through the enhancement of NRF2 mRNA translation and the increase of Nrf2 protein half-life [102, 103]. Nrf2 plays a central role in recruiting cellular defense systems against oxidative and electrophilic stress and in maintaining redox, lipid, and energy homeostasis. Cellular Nfr2 is sequestered in a cytosolic complex with the negative regulator Kelch-like ECH-associated protein 1 (Keap1). In one study, Nrf2 induction by the genetic knockdown of Keap1 increased hepatic FGF21 expression and plasma FGF21 levels in diabetic db/db mice and diet-induced obese mice [104]. A synthetic inducer of Nrf2 reproduced these effects in these mice. As a transcription factor, Nrf2 regulates antioxidant/electrophile responsive element (ARE/EpRE)-containing genes. Several ARE/EpREs were identified in the 5′-regulatory region of the mouse FGF21 gene [104]. However, chromatin immunoprecipitation (ChIP) analysis did not reveal significant Nrf2 binding [104].

Retinoic acid

Li et al. [30] identified FGF21 as a novel target gene of all-trans-retinoic acid (t-RA) through the action of the retinoic acid receptor (RAR). They showed that adenoviral overexpression of RARβ in mouse liver (i) stimulated hepatic mRNA and protein levels of FGF21, (ii) induced hepatic mRNA levels of carnitine palmitoyltransferase 1 α (CPT1α) (fatty acid catabolism), medium-chain acyl-CoA dehydrogenase (MCAD, a β-oxidation enzyme), 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2, a ketogenic enzyme), and 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL, also a ketogenic enzyme), (iii) increased plasma levels of ketone body and β-hydroxybutyrate, and iv) raised whole-body energy expenditure. These effects were consistent with the physiological response to fasting observed upon FGF21 administration, except that in the study of Li et al. [30], the mice were sacrificed while having free access to food. Li et al. [30] further identified a putative RAR response element (RARE) separated by one base (DR1) in the human FGF21 gene located at –645/–632, and two putative RARE sites spaced by five nucleotides (DR5) located at –537/–521 and –602/–586 in the regulatory region of the mouse FGF21 gene. The functional relevance of this RARE-like site was established when point mutations in the RARE abolished the transactivity of t-RA/RAR for the FGF21 gene. Moreover, the induction of FGF21 by the PPARα agonist, GW7647, combined with t-RA appeared to be synergistic. The knockdown of PPARα abolished GW7647-mediated induction of FGF21 gene expression, whereas the knockdown of RARβ did not, indicating that FGF21 transcription is independently upregulated by PPARα and RARβ [30].

The retinoic acid receptor-related receptors (RORs) also play an important regulatory role in lipid metabolism. RORs regulate gene expression by binding DNA as monomers to ROR response elements (ROREs) consisting of an AGGTCA half-site preceded by a 5′ AT-rich sequence. Wang et al. [105] identified a conserved classical RORE site positioned at –1563/–1554 in the 5′ regulatory region of the human FGF21 gene and –1223/–1213 upstream the mouse gene. This RORE site locates >1000-bp upstream of two additional putative proximally located RORE sites (–105/–96 and –88/–82 in the human FGF21 promoter, and –87/–78 and –69/–64 in the mouse FGF21 promoter). These proximal sites mediated REV-ERBα repression of the FGF21 gene in mouse primary hepatocytes [106].

Through their inductive and repressive activities, the first order clock-controlled genes RORs and REV-ERBs coordinate the circadian expression of FGF21 directly [105, 106] as well as indirectly through PPARα/FGF21 [107] (Figure 2). RORs and REV-ERBs are activated by the core clock genes aryl hydrocarbon receptor nuclear translocator-like protein 1 (BMAL1) and circadian locomotor output cycles kaput (CLOCK) and, in turn, provide feedback to the core clock genes BMAL1/CLOCK and period circadian protein homologue 1 (PER)/cryptochrome 1 (CRY) [108]. While the expression of FGF21 in the mouse liver exhibited a circadian rhythm, the oscillation pattern remains ill defined. Wild-type male Jcl:ICR mice had to be fed bezafibrate (a PPARα agonist) to exhibit temporal oscillation in the transcription of hepatic FGF21, which peaked at the time of the dark-to-light transition (ZT0, ZT is Zeitgeber time within a 24-h cycle composed of 12 h of light and 12 h of darkness). For comparison, the 24-h profile of FGF21 mRNA was flat in control Jcl:ICR mice not receiving bezafibrate [107]. In contrast, Tong et al. [109] found that, in C57BL6 mice, FGF21 mRNA peaked around circadian time CT6 in the first 24-h cycle and at CT12 in the second 24-h cycle. In the latter study, mice were maintained on a 12 h/12 h light/dark cycle with free access to food and water for 2 weeks prior to being transferred to the dark for 48 h. Under these conditions, mice were sacrificed every 4 h for two 24-h cycles. Hence, CT6 represents the 6-h time point after lights were turned on during the 2-week feeding. In this study, the oscillation of FGF21 mRNA was clearly anti-phase to that of E4-binding protein 4 gene (E4BP4), which encodes a bHLH-Zip transcription factor also called nuclear factor interleukin 3 regulated (NFIL3). E4BP4 has a role in the regulation of circadian rhythm by repressing the expression of a core clock gene periodic circadian protein homologue 1 (PER). E4BP4 is regulated by RORs and REV-ERBs, explaining why its circadian expression profile is in phase with that of BMAL1 and CLOCK [108, 110]. E4BP4 suppressed FGF21 gene expression by direct binding to a D-box element in the distal promoter (–1033 to –1015) [109]. In mouse liver, temporal FGF21 expression was low during the light phase and steadily increased during the dark phase (ZT12–ZT24) when the animals actively fed [111]. This profile was exacerbated in mice (TSC1lox/lox Alb-CreTg/0) in which liver mammalian target of rapamycin complex 1 (mTORC1) activity was induced by the knockdown of its repressor hamartin, also known as tuberous sclerosis 1 protein (TSC1) [111]. FGF21 expression was induced secondarily to PPARγ coactivator-1α (PGC-1α) activation in response to mTORC1-mediated depletion of glutamine in the liver. In these mice, RORα and RORγ expression displayed a circadian rhythm in phase with FGF21, while that of REV-ERBα and REV-ERBβ were anti-phase to FGF21.

Schematic representation of the role of first order clock-controlled genes in the circadian regulation of FGF21 gene expression. The model depicts the activating and repressing transcriptional activity of core clock protein complexes BMAL1/CLOCK and PER/CRY onto their own genes (the core circadian feedback loop) and first order clock-controlled genes (ROR, E4BP4, REV-ERB, PPARα) mediated by E-boxes. The model also depicts the activating and repressing transcriptional activity of first order clock-controlled genes onto the core clock genes and onto FGF21, a second order clock-controlled gene, mediated by RORE, D-box, and PPRE.
Figure 2:

Schematic representation of the role of first order clock-controlled genes in the circadian regulation of FGF21 gene expression.

The model depicts the activating and repressing transcriptional activity of core clock protein complexes BMAL1/CLOCK and PER/CRY onto their own genes (the core circadian feedback loop) and first order clock-controlled genes (ROR, E4BP4, REV-ERB, PPARα) mediated by E-boxes. The model also depicts the activating and repressing transcriptional activity of first order clock-controlled genes onto the core clock genes and onto FGF21, a second order clock-controlled gene, mediated by RORE, D-box, and PPRE.

Polyphenol (curcumin)

Curcumin is the major polyphenol pigment isolated from the plant Curcuma longa, commonly known as turmeric. Curcumin has a variety of pharmacologic properties. It has been demonstrated to have systemic anti-inflammatory activity and beneficial effects in several types of cancers both in animals and humans [112117], and in individuals with dermatitis [118], Crohn’s disease [119], and ulcerative colitis [120]. In addition, curcumin has been shown to improve metabolic disorders associated with hyperlipidemia and hyperglycemia [121125]. Curcumin gavage to mice stimulated FGF21 expression in liver [126]. A small dose of curcumin (2 μM) also increased FGF21 protein abundance in mouse primary hepatocytes and human hepatocellular carcinoma HepG2 cells [126]. The underlying transcriptional mechanism is currently unknown and should be a matter of further investigation.

Expert opinion

Recombinant FGF21 (rFGF21) administration is an experimental polypeptide therapy against type 2 diabetes and lipid anomalies. However, the high costs of producing rFGF21 and the mode of delivery by injection are important limitations to the wide therapeutic use of engineered FGF21. The stimulation of endogenous FGF21 production through diet should be explored as a practical and cost-effective alternative approach. Among dietary factors, high dextrose, low protein, methionine restriction, short-chain fatty acids (butyric acid and lipoic acid), and all-trans-retinoic acid have been shown to induce FGF21 expression and circulating levels. These effects, though, are usually more pronounced in liver tissue and isolated hepatocytes than they are in adipose tissue and isolated fat cells. This observation calls for further investigation of the regulation of the FGF21 gene in non-hepatic tissues by dietary and non-dietary compounds. If new approaches were to emerge from this research, they could be combined with liver-effective strategies to assess broader efficacy.

Outlook

Given that all macronutrients and a growing list of structurally diverse dietary molecules have been shown to regulate FGF21 transcription in recent years, it is likely that other dietary compounds will be shown to alter FGF21 gene expression in the future. Regulation of FGF21 transcripts by non-coding RNAs is expected to develop from its current rudimentary beginnings. It is expected that further research will be devoted to elucidate the cause and significance of interindividual variations in serum FGF21 levels among human subjects.

Highlights

  • Anti-miR-577-based approaches may boost the insulinotropic action of FGF21.

  • CREBH and PPARα synergize to activate FGF21 gene expression through the binding of the CREBH-PPARα-RXR complex.

  • Glucagon and insulin can cooperate to induce FGF21 expression in liver cells.

  • FGF21 gene expression is upregulated by the eIF2α/ATF4/CHOP and the IRE1α/XBP1 branches of the UPR.

  • PPARα and RARβ can transactivate the FGF21 gene synergistically.

  • E4BP4 (also known as NFIL3) represses FGF21 gene expression and regulates its circadian oscillation.

  • The nutritional and physiological factors influencing the response of the FGF21 gene to high-fat diet need further studies.

  • The transcriptional mechanism of butyric acid on FGF21 expression requires further investigation.

Acknowledgments:

Funding was provided in part by the University of Nebraska-Lincoln ARD Hatch Act, Allen Foundation (2013-403), and USDA-NIFA (2015-05502). The authors have declared no conflict of interest.

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About the article

Received: 2016-03-28

Accepted: 2016-05-08

Published Online: 2016-06-10


Funding Source: University of Nebraska-Lincoln

Award identifier / Grant number: 2013-403

Funding was provided in part by the University of Nebraska-Lincoln ARD Hatch Act, Allen Foundation (2013-403), and USDA-NIFA (2015-05502). The authors have declared no conflict of interest.


Citation Information: Hormone Molecular Biology and Clinical Investigation, Volume 30, Issue 1, 20160016, ISSN (Online) 1868-1891, ISSN (Print) 1868-1883, DOI: https://doi.org/10.1515/hmbci-2016-0016.

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