The Orphan Nuclear Receptor ERRγ Regulates Hepatic CB1 Receptor-Mediated Fibroblast Growth Factor 21 Gene Expression

The fasting-induced hepatic hormone, fibroblast growth factor 21 (FGF21), is a potential candidate for the treatment of metabolic syndromes. Although peroxisome proliferator-activated receptor (PPAR)α is known to play a major role in the induction of hepatic FGF21 expression, other fasting-induced transcription factors that induce FGF21 expression have not yet been fully studied. In the present study, we investigated whether the fasting-induced activation of the orphan nuclear receptor Nur77 increases hepatic FGF21 expression. We found that fasting induced hepatic Nur77 and FGF21 expression. Glucagon and forskolin increased Nur77 and FGF21 expression in vivo and in vitro, respectively, and adenovirus-mediated overexpression of Nur77 (Ad-Nur77) increased FGF21 expression in vitro and in vivo. Moreover, knockdown of endogenous Nur77 expression by siRNA-Nur77 abolished the effect of forskolin on FGF21 expression. The results of ChIP assays, EMSA, and mutagenesis analysis showed that Nur77 bound to the putative NBRE of the FGF21 promoter in cultured hepatocytes and fasting induced Nur77 binding to the FGF21 promoter in vivo. Knockdown of PPARα partially inhibited forskolin-induced FGF21 expression, suggesting PPARα involvement in glucagon-stimulated FGF21 expression. In addition, double knockdown of PPARα and Nur77 further diminished FGF21 expression in cultured hepatocytes. In conclusion, this study shows that Nur77 mediates fasting-induced hepatic FGF21 expression, and suggests an alternative mechanism via which hepatic FGF21 transcription is mediated under fasting conditions.

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Transmembrane G protein-coupled receptor 5 signaling stimulates fibroblast growth factor 21 expression concomitant with up-regulation of the transcription factor nuclear receptor Nr4a1

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2021.112078 ◽

2021 ◽

Vol 142 ◽

pp. 112078

Author(s):

Genki Kiyama ◽

Ken-ichi Nakashima ◽

Kazumasa Shimada ◽

Naoko Murono ◽

Wataru Kakihana ◽

...

Keyword(s):

Transcription Factor ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

G Protein ◽

Nuclear Receptor ◽

Fibroblast Growth Factor 21 ◽

Fibroblast Growth ◽

G Protein Coupled Receptor ◽

G Protein Coupled

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Fasting decreases plasma FGF21 in obese subjects and the expression of FGF21 receptors in adipose tissue in both lean and obese subjects

Journal of Endocrinology ◽

10.1530/joe-18-0002 ◽

2018 ◽

Vol 239 (1) ◽

pp. 73-80 ◽

Cited By ~ 10

Author(s):

Eva B Nygaard ◽

Cathrine Ørskov ◽

Thomas Almdal ◽

Henrik Vestergaard ◽

Birgitte Andersen

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Lipid Metabolism ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 21 ◽

Fibroblast Growth ◽

Adipose Tissues ◽

Blood Samples ◽

Obese Subjects

Fibroblast growth factor 21 (FGF21) is a metabolic regulator of energy and lipid metabolism. FGF21 is highly expressed in liver while FGF21 receptors (beta-klotho (KLB) and FGFR1c) are highly expressed in white adipose tissues (WATs). Plasma FGF21 has been shown to be increased after 7–10 days of fasting but oppositely plasma FGF21 is also increased in obesity. The aim of this study was to measure the effect of 60 h of fasting on plasma FGF21 levels in obese and lean subjects and to determine the gene expression of KLB and FGFR1c in the subcutaneous WAT before, during and after 60 h of fasting. Eight obese (BMI >30 kg/m2) and seven lean subjects (BMI <25 kg/m2) were fasted for 60 h and blood samples were taken at time 0 and after 12, 36 and 60 h of fasting. A biopsy from the subcutaneous WAT was taken at time 0, 12 and 60 h of fasting. FGF21 was measured in plasma by an ELISA and mRNA expression of KLB and FGFR1c was measured in WAT by quantitative PCR (qPCR). The fast significantly decreased plasma FGF21 in obese subjects while no change in plasma FGF21 was observed in lean subjects. Interestingly, KLB was significantly decreased in WAT in response to fasting in both lean and obese subjects indicating a potential important adaptive regulation of KLB in response to fasting.

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FGF21 (Fibroblast Growth Factor 21) Defines a Potential Cardiohepatic Signaling Circuit in End-Stage Heart Failure

Circulation Heart Failure ◽

10.1161/circheartfailure.121.008910 ◽

2021 ◽

Author(s):

Salah Sommakia ◽

Naredos H. Almaw ◽

Sandra H. Lee ◽

Dinesh K.A. Ramadurai ◽

Iosif Taleb ◽

...

Keyword(s):

Gene Expression ◽

Heart Failure ◽

Growth Factor ◽

Ejection Fraction ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 21 ◽

Fibroblast Growth ◽

Reduced Ejection Fraction ◽

End Stage ◽

Signaling Circuit

Background: Extrinsic control of cardiomyocyte metabolism is poorly understood in heart failure (HF). FGF21 (Fibroblast growth factor 21), a hormonal regulator of metabolism produced mainly in the liver and adipose tissue, is a prime candidate for such signaling. Methods: To investigate this further, we examined blood and tissue obtained from human subjects with end-stage HF with reduced ejection fraction at the time of left ventricular assist device implantation and correlated serum FGF21 levels with cardiac gene expression, immunohistochemistry, and clinical parameters. Results: Circulating FGF21 levels were substantially elevated in HF with reduced ejection fraction, compared with healthy subjects (HF with reduced ejection fraction: 834.4 [95% CI, 628.4–1040.3] pg/mL, n=40; controls: 146.0 [86.3–205.7] pg/mL, n=20, P =1.9×10 −5 ). There was clear FGF21 staining in diseased cardiomyocytes, and circulating FGF21 levels negatively correlated with the expression of cardiac genes involved in ketone metabolism, consistent with cardiac FGF21 signaling. FGF21 gene expression was very low in failing and nonfailing hearts, suggesting extracardiac production of the circulating hormone. Circulating FGF21 levels were correlated with BNP (B-type natriuretic peptide) and total bilirubin, markers of chronic cardiac and hepatic congestion. Conclusions: Circulating FGF21 levels are elevated in HF with reduced ejection fraction and appear to bind to the heart. The liver is likely the main extracardiac source. This supports a model of hepatic FGF21 communication to diseased cardiomyocytes, defining a potential cardiohepatic signaling circuit in human HF.

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Th2 Cytokines Increase the Expression of Fibroblast Growth Factor 21 in the Liver

Cells ◽

10.3390/cells10061298 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1298

Author(s):

Seul-Gi Kang ◽

Seong-Eun Lee ◽

Min-Jeong Choi ◽

Joon-Young Chang ◽

Jung-Tae Kim ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Intraperitoneal Administration ◽

Janus Kinase ◽

Fibroblast Growth Factor 21 ◽

Dependent Manner ◽

Th2 Cytokines ◽

Fibroblast Growth

Interleukin-4 (IL-4) and IL-13 are the major T helper 2 (Th2) cytokines, and they are involved in the regulation of metabolism in the adipose tissue. The liver contains diverse innate and adaptive immune cells, but it remains to be determined whether Th2 cytokines modulate energy metabolism in the liver. Here, using gene expression data from the Gene Expression Omnibus (GEO) and the BXD mouse reference population, we determined that the Th2 cytokines IL-4 and IL-13 increase the secretion of fibroblast growth factor 21 (FGF21) in the liver. In vitro experiments confirmed that FGF21 was highly expressed in response to IL-4 and IL-13, and this response was abolished by the Janus kinase (JAK)-signal transducer and activator of transcription 6 (STAT6) blockade. Moreover, FGF21 expression in response to Th2 cytokines was augmented by selective peroxisome proliferator-activated receptor α (PPARα) inhibition. In vivo administration of IL-4 increased FGF21 protein levels in the liver in a STAT6-dependent manner, but FGF21 secretion in response to IL-4 was not observed in the epididymal white adipose tissue (eWAT) despite the activation of STAT6. Intraperitoneal administration of IL-33, an activator of type 2 immune responses, significantly increased the level of FGF21 in the serum and liver after 24 h, but repeated administration of IL-33 attenuated this effect. Taken together, these data demonstrate that the IL-4/IL-13–STAT6 axis regulates metabolic homeostasis through the induction of FGF21 in the liver.

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Reciprocal Effects of Antiretroviral Drugs Used To Treat HIV Infection on the Fibroblast Growth Factor 21/β-Klotho System

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00029-18 ◽

2018 ◽

Vol 62 (6) ◽

pp. e00029-18 ◽

Cited By ~ 3

Author(s):

Ricardo Moure ◽

Pere Domingo ◽

Joan Villarroya ◽

Laura Gasa ◽

José M. Gallego-Escuredo ◽

...

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Growth Factor ◽

Reverse Transcriptase ◽

Fibroblast Growth Factor ◽

Antiretroviral Drugs ◽

Fibroblast Growth Factor 21 ◽

Target Cells ◽

Fibroblast Growth ◽

Drug Treatments

ABSTRACT Following antiretroviral therapy, HIV-infected patients show increased circulating levels of the antidiabetic hormone fibroblast growth factor 21 (FGF21). In contrast, the expression of the FGF21-obligatory coreceptor β-Klotho (KLB) is reduced in target tissues. This situation is comparable to the FGF21 resistance status observed in obesity and type 2 diabetes. Here, we performed the first systematic study of the effects of distinct members of different antiretroviral drug classes on the FGF21/KLB system in human hepatic, adipose, and skeletal muscle cells. Most protease inhibitors and the nonnucleoside reverse transcriptase inhibitor efavirenz induced FGF21 gene expression. Neither nucleoside reverse transcriptase inhibitors nor the viral entry inhibitor maraviroc had any effect. Among the integrase inhibitors, elvitegravir significantly induced FGF21 expression, whereas raltegravir had minor effects only in adipose cells. In human hepatocytes and adipocytes, known target cells of FGF21 action, efavirenz, elvitegravir, and the lopinavir-ritonavir combination exerted inhibitory effects on KLB gene expression. Drug treatments that elicited FGF21 induction/KLB repression were those found to induce endoplasmic reticulum (ER) stress and oxidative stress. Notably, the pharmacological agents thapsigargin and tunicamycin, which induce these stress pathways, mimicked the effects of drug treatments. Moreover, pharmacological inhibitors of either ER or oxidative stress significantly impaired lopinavir–ritonavir-induced regulation of FGF21, but not KLB. In conclusion, the present in vitro screen study identifies the antiretroviral drugs that affect FGF21/KLB expression in human cells. The present results could have important implications for the management of comorbidities resulting from side effects of specific antiretroviral drugs for the treatment of HIV-infected patients.

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The regulation of FGF21 gene expression by metabolic factors and nutrients

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2016-0016 ◽

2016 ◽

Vol 30 (1) ◽

Cited By ~ 4

Author(s):

Anjeza Erickson ◽

Régis Moreau

Keyword(s):

Gene Expression ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 21 ◽

Fibroblast Growth ◽

Metabolic Factors

AbstractFibroblast growth factor 21 (

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Fibroblast Growth Factor 21 and Thyroid Hormone Show Mutual Regulatory Dependency but Have Independent Actions In Vivo

Endocrinology ◽

10.1210/en.2013-1902 ◽

2014 ◽

Vol 155 (5) ◽

pp. 2031-2040 ◽

Cited By ~ 19

Author(s):

Eleni M. Domouzoglou ◽

ffolliott Martin Fisher ◽

Inna Astapova ◽

Elliott C. Fox ◽

Alexei Kharitonenkov ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Growth Factor ◽

Thyroid Hormone ◽

Fibroblast Growth Factor ◽

Knockout Mice ◽

Fibroblast Growth Factor 21 ◽

Fibroblast Growth ◽

Brown Adipose ◽

Circulating Levels

Thyroid hormone (TH) regulates fibroblast growth factor 21 (FGF21) levels in the liver and in the adipose tissue. In contrast, peripheral FGF21 administration leads to decreased circulating levels of TH. These data suggest that FGF21 and TH could interact to regulate metabolism. In the present study, we confirmed that TH regulates adipose and hepatic FGF21 expression and serum levels in mice. We next investigated the influence of TH administration on key serum metabolites, gene expression in the liver and brown adipose tissue, and energy expenditure in FGF21 knockout mice. Surprisingly, we did not observe any significant differences in the effects of TH on FGF21 knockout mice compared with those in wild-type animals, indicating that TH acts independently of FGF21 for the specific outcomes studied. Furthermore, exogenous FGF21 administration to hypothyroid mice led to similar changes in serum and liver lipid metabolites and gene expression in both hypothyroid and euthyroid mice. Thus, it appears that FGF21 and TH have similar actions to decrease serum and liver lipids despite having some divergent regulatory effects. Whereas TH leads to up-regulation in the liver and down-regulation in brown adipose tissue of genes involved in the lipid synthesis pathway (eg, fatty acid synthase (FASN) and SPOT14), FGF21 leads to the opposite changes in expression of these genes. In conclusion, TH and FGF21 act independently on the outcomes studied, despite their ability to regulate each other's circulating levels. Thus, TH and FGF21 may modulate the availability of each other in critical metabolic states.

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Integrated Regulation of Hepatic Metabolism by Fibroblast Growth Factor 21 (FGF21) in Vivo

Endocrinology ◽

10.1210/en.2011-0281 ◽

2011 ◽

Vol 152 (8) ◽

pp. 2996-3004 ◽

Cited By ~ 147

Author(s):

ffolliott M. Fisher ◽

Jennifer L. Estall ◽

Andrew C. Adams ◽

Patrick J. Antonellis ◽

Holly A. Bina ◽

...

Keyword(s):

Gene Expression ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Serum Insulin ◽

Hepatic Metabolism ◽

Hepatic Function ◽

Fibroblast Growth Factor 21 ◽

Fibroblast Growth ◽

Hepatic Expression

Fibroblast growth factor (FGF21) plays an important role in regulating hepatic oxidation of fatty acids and gluconeogenesis in response to fasting and during consumption of a ketogenic diet. However, the metabolic pathways through which FGF21 regulates hepatic function are not well defined. To identify the effects of FGF21 on the liver in vivo, we administered FGF21 to mice and analyzed acute effects on signaling and gene expression. We found that FGF21 acts directly on the liver to stimulate phosphorylation of fibroblast growth factor receptor substrate 2 and ERK1/2. Acute FGF21 treatment induced hepatic expression of key regulators of gluconeogenesis, lipid metabolism, and ketogenesis including glucose-6-phosphatase, phosphoenol pyruvate carboxykinase, 3-hydroxybutyrate dehydrogenase type 1, and carnitine palmitoyltransferase 1α. In addition, injection of FGF21 was associated with decreased circulating insulin and free fatty acid levels. FGF21 treatment induced mRNA and protein expression of peroxisome proliferator-activated receptor-γ coactivator (PGC-1α), suggesting that PGC-1α may play a role in regulating FGF21 action. However, studies using mice with liver-specific ablation of PGC-1α revealed the same regulation of gluconeogenic gene expression by FGF21 as seen in wild-type mice, indicating that PGC-1α is not necessary for the effect of FGF21 on glucose metabolism. These data demonstrate that FGF21 acts directly on the liver to modulate hepatic metabolism. The direct effects we examined are not dependent on PGC-1α. In addition, FGF21 treatment is associated with decreased serum insulin levels that my affect hepatic function.

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Growth Hormone Stimulates Transcription of the Fibroblast Growth Factor 21 Gene in the Liver through the Signal Transducer and Activator of Transcription 5

Endocrinology ◽

10.1210/en.2011-1591 ◽

2012 ◽

Vol 153 (2) ◽

pp. 750-758 ◽

Cited By ~ 33

Author(s):

Jie Yu ◽

Lidan Zhao ◽

Aihua Wang ◽

Satyanarayana Eleswarapu ◽

Xiaomei Ge ◽

...

Keyword(s):

Gene Expression ◽

Growth Factor ◽

Mrna Expression ◽

Fibroblast Growth Factor ◽

Janus Kinase ◽

Fibroblast Growth Factor 21 ◽

Dependent Manner ◽

Fibroblast Growth ◽

Signal Transducer ◽

Gh Receptor

Fibroblast growth factor 21 (FGF21) is a recently discovered metabolic regulator. Interestingly, FGF21 is also known to inhibit Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) signaling from the GH receptor in the liver, where FGF21 mRNA is predominantly expressed. In this study, we tested the hypothesis that FGF21 gene expression in the liver is controlled by GH through STAT5. We found that GH injection to cattle increased FGF21 mRNA expression in the liver. Mapped by a 5′-rapid amplification of cDNA ends assay, transcription of the FGF21 gene in the bovine liver was mainly initiated from a nucleotide 24 bp downstream of a TATA box. The bovine FGF21 promoter contains three putative STAT5-binding sites. EMSA confirmed the ability of them to bind to liver STAT5 protein from GH-injected cattle. Chromatin immunoprecipitation assays demonstrated that GH administration increased the binding of STAT5 to the FGF21 promoter in the liver. Cotransfection analyses showed that GH induced reporter gene expression from the FGF21 promoter in a STAT5-dependent manner. GH also stimulated FGF21 mRNA expression in cultured mouse hepatocytes. These data together indicate that GH directly stimulates FGF21 gene transcription in the liver, at least in part, through STAT5. This finding, together with the fact that FGF21 inhibits GH-induced JAK2-STAT5 signaling in the liver, suggests a novel negative feedback loop that prevents excessive JAK2-STAT5 signaling from the GH receptor in the liver.

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