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

2018 ◽  
Vol 62 (6) ◽  
pp. e00029-18 ◽  
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.

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

PLoS ONE ◽  
2016 ◽  
Vol 11 (7) ◽  
pp. e0159425 ◽  
Author(s):  
Yoon Seok Jung ◽  
Ji-Min Lee ◽  
Don-Kyu Kim ◽  
Yong-Soo Lee ◽  
Ki-Sun Kim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Nuclear Receptor ◽  
Cb1 Receptor ◽  
Fibroblast Growth Factor 21 ◽  
Orphan Nuclear Receptor ◽  
Fibroblast Growth

scholarly journals MicroRNA-Regulated Rickettsial Invasion into Host Endothelium via Fibroblast Growth Factor 2 and Its Receptor FGFR1

Cells ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 240 ◽  
Author(s):  
Abha Sahni ◽  
Hema Narra ◽  
Jignesh Patel ◽  
Sanjeev Sahni
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Host Cells ◽  
Microvascular Endothelial Cells ◽  
Target Cells ◽  
Fibroblast Growth ◽  
Wide Range ◽  
Microvascular Endothelial

Microvascular endothelial cells (ECs) represent the primary target cells during human rickettsioses and respond to infection via the activation of immediate–early signaling cascades and the resultant induction of gene expression. As small noncoding RNAs dispersed throughout the genome, microRNAs (miRNAs) regulate gene expression post-transcriptionally to govern a wide range of biological processes. Based on our recent findings demonstrating the involvement of fibroblast growth factor receptor 1 (FGFR1) in facilitating rickettsial invasion into host cells and published reports suggesting miR-424 and miR-503 as regulators of FGF2/FGFR1, we measured the expression of miR-424 and miR-503 during R. conorii infection of human dermal microvascular endothelial cells (HMECs). Our results revealed a significant decrease in miR-424 and miR-503 expression in apparent correlation with increased expression of FGF2 and FGFR1. Considering the established phenomenon of endothelial heterogeneity and pulmonary and cerebral edema as the prominent pathogenic features of rickettsial infections, and significant pathogen burden in the lungs and brain in established mouse models of disease, we next quantified miR-424 and miR-503 expression in pulmonary and cerebral microvascular ECs. Again, R. conorii infection dramatically downregulated both miRNAs in these tissue-specific ECs as early as 30 min post-infection in correlation with higher FGF2/FGFR1 expression. Changes in the expression of both miRNAs and FGF2/FGFR1 were next confirmed in a mouse model of R. conorii infection. Furthermore, miR-424 overexpression via transfection of a mimic into host ECs reduced the expression of FGF2/FGFR1 and gave a corresponding decrease in R. conorii invasion, while an inhibitor of miR-424 had the expected opposite effect. Together, these findings implicate the rickettsial manipulation of host gene expression via regulatory miRNAs to ensure efficient cellular entry as the critical requirement to establish intracellular infection.

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

2018 ◽  
Vol 239 (1) ◽  
pp. 73-80 ◽  
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.

scholarly journals Fibroblast Growth Factor 21 Ameliorates Hyperuricemic Nephropathy by Improving Oxidative Stress through Activating Akt/Nrf2 Signaling Pathway

2021 ◽  
Author(s):  
Xinghao Jiang ◽  
Yimeng Zou ◽  
Yeboah Kwaku Opoku ◽  
Shijie Liu ◽  
Dan Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Therapeutic Effect ◽  
Knockout Mice ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Glomerular Mesangial Cells ◽  
Nrf2 Signaling Pathway

Abstract Epidemiological investigations have shown an elevated expression of fibroblast growth factor 21 (FGF21) in the serum of patients with hyperuricemia. However, the effect of FGF21 on hyperuricemic nephropathy is still unknown. The purpose of this study, therefore, was to explore the effect and mechanism of action of FGF21 on hyperuricemic nephropathy. The level of FGF21 in PBMCs was determined in 10 patients with hyperuricemic nephropathy. Hyperuricemic mice models were induced in wild-type C57BL/6 and FGF21 knockout mice. Six mice in each group were treated with FGF21 at a dose of 1mg/kg and 5mg/kg for 30 days. For the in vitro studies, glomerular mesangial cells were exposed to lipopolysaccharide and monosodium uric acid to induce inflammation. This was followed by treatment with 100nM, 1000nM of FGF21 for 72 h to observe the therapeutic effect. The levels of FGF21 in patients with hyperuricemic nephropathy were elevated. Also, FGF21 knockout mice experienced more severe nephropathy compared to the WT mice. This was characterized by an increase in inflammatory factors and fibrosis in the kidney, which was reversed by exogenous FGF21 treatment. FGF21 recorded a significant therapeutic effect through the activation of Akt/Nrf2 signal pathway in both in vivo and in vitro studies. However, the effect increasing effect of FGF21 on Nrf2 was reduced by the addition of Akt inhibitor GSK690693. In conclusion, our study found for the first time that FGF21 can significantly improve hyperuricemic nephropathy through the promotion of the Akt/Nrf2 signalling pathway leading to improvement in oxidative stress.

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

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.

scholarly journals Fibroblast Growth Factor 21 Protects Against Atrial Remodeling via Reducing Oxidative Stress

2021 ◽  
Vol 8 ◽  
Author(s):  
Miao Chen ◽  
Jiawei Zhong ◽  
Zhen Wang ◽  
Hongfei Xu ◽  
Heng Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Atrial Fibrillation ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 21 ◽  
Atrial Remodeling ◽  
Protective Effects ◽  
Fibroblast Growth ◽  
Atrial Myocytes ◽  
Antioxidant Genes

Aim: The structural and electrical changes in the atrium, also known as atrial remodeling, are the main characteristics of atrial fibrillation (AF). Fibroblast growth factor 21 (Fgf21) is an important endocrine factor, which has been shown to play an important role in cardiovascular diseases. However, the effects of Fgf21 on atrial remodeling have not been addressed yet. The purpose of the present study is to evaluate the effects of Fgf21 on atrial remodeling.Methods and Results: Adult mice were treated with Ang II, and randomly administrated with or without Fgf21 for 2 weeks. The susceptibility to AF was assessed by electrical stimulation and optical mapping techniques. Here, we found that Fgf21 administration attenuated the inducibility of atrial fibrillation/atrial tachycardia (AF/AT), improved epicardial conduction velocity in the mice atria. Mechanistically, Fgf21 protected against atrial fibrosis and reduced oxidative stress of the atria. Consistently, in vitro study also demonstrated that Fgf21 blocked the upregulation of collagen by Tgf-β in fibroblasts and attenuated tachypacing-induced oxidative stress including reactive oxygen species (ROS), Tgf-β, and ox-CaMKII in atrial myocytes. We further found that Fgf21 attenuated oxidative stress by inducing antioxidant genes, such as SOD2 and UCP3. Fgf21 also improved tachypacing-induced myofibril degradation, downregulation of L-type calcium channel, and upregulation of p-RyR2, which implicated protective effects of Fgf21 on structural and electrical remodeling in the atria. Moreover, Nrf2 was identified as a downstream of Fgf21 and partly mediated Fgf21-induced antioxidant gene expression in atrial myocytes.Conclusion: Fgf21 administration effectively suppressed atrial remodeling by reducing oxidative stress, which provides a novel therapeutic insight for AF.

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