Fibroblast growth factor 21 plays an inhibitory role in vascular calcification in vitro through OPG/RANKL system

2017 ◽  
Vol 491 (3) ◽  
pp. 578-586 ◽  
Author(s):  
Fangying Cao ◽  
Xiaoxiao Liu ◽  
Xiangrong Cao ◽  
Shaoping Wang ◽  
Kun Fu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Vascular Calcification ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Inhibitory Role

scholarly journals Fibroblast growth factor-21 serum concentrations are associated with metabolic and hepatic markers in humans

2012 ◽  
Vol 216 (2) ◽  
pp. 135-143 ◽  
Author(s):  
Susan Kralisch ◽  
Anke Tönjes ◽  
Kerstin Krause ◽  
Judit Richter ◽  
Ulrike Lossner ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Serum Concentrations ◽  
The Metabolic Syndrome ◽  
Glutamyl Transferase ◽  
Culture Supernatants

Rather than a traditional growth factor, fibroblast growth factor-21 (FGF21) is considered to be a metabolic hormone. In the current study, we investigated serum FGF21 levels in the self-contained population of Sorbs. Serum FGF21 concentrations were quantified by ELISA and correlated with IGF1 as well as metabolic, renal, hepatic, inflammatory, and cardiovascular parameters in 913 Sorbs from Germany. Moreover, human IGF1 protein secretion was investigated in FGF21-stimulated HepG2 cells. Median FGF21 serum concentrations were 2.1-fold higher in subjects with type 2 diabetes mellitus (141.8 ng/l) compared with controls (66.7 ng/l). Furthermore, nondiabetic subjects with FGF21 levels below the detection limit of the ELISA showed a more beneficial metabolic profile compared with subjects with measurable FGF21. Moreover, FGF21 was significantly lower in female compared with male subjects after adjustment for age and BMI. In multiple regression analyses, circulating FGF21 concentrations remained independently and positively associated with gender, systolic blood pressure, triglycerides, and γ glutamyl transferase whereas a negative association was observed with IGF1 in nondiabetic subjects. Notably, FGF21 significantly inhibited IGF1 secretion into HepG2 cell culture supernatants in preliminary in vitro experiments. FGF21 serum concentrations are associated with facets of the metabolic syndrome, hepatocellular function, as well as GH status.

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.

scholarly journals Fibroblast Growth Factor 21 Ameliorates NaV1.5 and Kir2.1 Channel Dysregulation in Human AC16 Cardiomyocytes

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiamin Li ◽  
Yuanshi Li ◽  
Yining Liu ◽  
Hang Yu ◽  
Ning Xu ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Ventricular Arrhythmias ◽  
Sodium Current ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Serum Samples

Infarcted myocardium is predisposed to cause lethal ventricular arrhythmias that remain the main cause of death in patients suffering myocardial ischemia. Liver-derived fibroblast growth factor 21 (FGF21) is an endocrine regulator, which exerts metabolic actions by favoring glucose and lipids metabolism. Emerging evidence has shown a beneficial effect of FGF21 on cardiovascular diseases, but the role of FGF21 on ventricular arrhythmias following myocardial infarction (MI) in humans has never been addressed. This study was conducted to investigate the pharmacological effects of FGF21 on cardiomyocytes after MI in humans. Patients with arrhythmia in acute MI and healthy volunteers were enrolled in this study. Serum samples were collected from these subjects on day 1 and days 7–10 after the onset of MI for measuring FGF21 levels using ELISA. Here, we found that the serum level of FGF21 was significantly increased on day 1 after the onset of MI and it returned to normal on days 7–10, relative to the Control samples. In order to clarify the regulation of FGF21 on arrhythmia, two kinds of arrhythmia animal models were established in this study, including ischemic arrhythmia model (MI rat model) and nonischemic arrhythmia model (ouabain-induced guinea pig arrhythmia model). The results showed that the incidence and duration time of ischemic arrhythmias in rhbFGF21-treated MI rats were significantly reduced at different time point after MI compared with normal saline-treated MI rats. Moreover, the onset of the first ventricular arrhythmias was delayed and the numbers of VF and maintenance were attenuated by FGF21 compared to the rhbFGF21-untreated group in the ouabain model. Consistently, in vitro study also demonstrated that FGF21 administration was able to shorten action potential duration (APD) in hydrogen peroxide-treated AC16 cells. Mechanically, FGF21 can ameliorate the electrophysiological function of AC16 cells, which is characterized by rescuing the expression and dysfunction of cardiac sodium current (INa) and inward rectifier potassium (Ik1) in AC16 cells induced by hydrogen peroxide. Moreover, the restorative effect of FGF21 on NaV1.5 and Kir2.1 was eliminated when FGF receptors were inhibited. Collectively, FGF21 has the potential role of ameliorating transmembrane ion channels remodeling through the NaV1.5/Kir2.1 pathway by FGF receptors and thus reducing life-threatening postinfarcted arrhythmias, which provides new strategies for antiarrhythmic therapy in clinics.

Effects of fibroblast growth factor 21 on cell damage in vitro and atherosclerosis in vivo

2014 ◽  
Vol 92 (11) ◽  
pp. 927-935 ◽  
Author(s):  
Wenhe Zhu ◽  
Changwen Wang ◽  
Lei Liu ◽  
Yan Li ◽  
Xiaokun Li ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Cell Damage ◽  
Density Lipoprotein ◽  
Serum Levels ◽  
Lipoprotein Cholesterol ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth

Fibroblast growth factor 21 (FGF-21), which is a modulator of glucose and lipid homeostasis, acts as a novel therapeutic reagent for many metabolic perturbations. However, its potential as a treatment for cardiovascular disease, especially atherosclerosis (AS) has not been fully explored. Here, we report that recombinant FGF-21 improves resistance to cell damage from oxidative stress in vitro, and from atherosclerosis in vivo. Human umbilical vein endothelial cells (HUVECs) were induced with H2O2, followed by treatment with high purity recombinant FGF-21. The results indicated that FGF-21 significantly enhanced cell viability and decreased the degree of DNA fragmentation in HUVECs, as caused by H2O2 stress induction. Further studies revealed that FGF-21 inhibited H2O2-induced cell apoptosis by preventing the activation of mitogen-activated protein kinase (MAPK) signaling pathways. In an established rat model, FGF-21 dramatically improved the condition of atherosclerotic rats by decreasing serum levels of total triglyceride (TG), low density lipoprotein cholesterol (LDL-C), and total cholesterol (TC), and by increasing the serum levels of high density lipoprotein cholesterol (HDL-C). FGF-21 also has antioxidant effects in the atherosclerotic rat, such that increased levels of superoxide dismutase, reduced glutathione, and reduced malondialdehyde were observed. These data provide novel insight into the potential use of FGF-21 in the prevention and treatment of human cardiovascular diseases.

scholarly journals Fibroblast Growth Factor 21 Predicts and Promotes Vascular Calcification in Haemodialysis Patients

2020 ◽  
Author(s):  
Liqiong Jiang ◽  
Qing Yin ◽  
Min Yang ◽  
Min Li ◽  
Mingming Pan ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Thoracic Aorta ◽  
Vascular Calcification ◽  
Calcium Deposition ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Mineral Density ◽  
Mesenchymal Transition

Abstract Background: Cardiovascular disease (CVD) is the leading cause of death in haemodialysis (HD) patients. Vascular calcification (VC) is dramatically accelerated and is strongly associated with CVD events and mortality in HD patients. VC coexists with osteoporosis in many studies. Fibroblast growth factor 21 (FGF21) as an adipocytokines is a new hypoglycemic strategy and is inversely related to bone mineral density.Methods: To evaluate the contribution of FGF21 to VC in HD patients, we preliminary sreened 802 HD patients of two large HD centers in China. At last 388 HD patients were entered this cross-sectional study. We detected circulating FGF21 levels and measured the whole thoracic aorta calcification scores (TACS) and calcification scores of the three segments of thoracic aorta (TA), including ascending thoracic aorta (ATACS), aortic arch (AoACS), and descending thoracic aorta (DTACS) of our 388 HD patients. In addition, we pre-incubated human aortic endothelial cells (HAECs) with FGF21 in the presence or absence of parathyroid hormone (PTH) in vitro.Results: The median serum FGF21 level in HD patients was 11-fold higher than that in healthy controls. Ln(FGF21) was positively correlated with Ln(TACS+1), Ln(ATACS+1), Ln(AoACS+1) and Ln(DTACS+1) respectively in HD patients. Serum FGF21 was independently associated with TACS and ATACS, AoACS, and DTACS. FGF21 combined with age, calcium and intact parathyroid hormone demonstrated a high area under the curve (AUC=0.84) with optimal sensitivity (84%) and specificity (71%) for the prediction of VC in HD patients. Our vitro results showed that FGF21 enhanced the calcification effect of PTH on HAECs by increasing calcium deposition and endothelial-to-mesenchymal transition (EndMT).Conclusions: Circulating FGF21 was notably higher and was a potential predictor and promoter of VC in HD patients.Trial registration Chinese Clinical Trial Registry, identifier: ChiCTR1900028249. Registered 16 December 2019-Retrospectively registered,http://www.medresman.org.cn/uc/project/projectedit.aspx?proj=5981

scholarly journals Orphan Nuclear Receptor Nur77 Mediates Fasting-Induced Hepatic Fibroblast Growth Factor 21 Expression

Endocrinology ◽  
2014 ◽  
Vol 155 (8) ◽  
pp. 2924-2931 ◽  
Author(s):  
Ae-Kyung Min ◽  
Kwi-Hyun Bae ◽  
Yun-A Jung ◽  
Yeon-Kyung Choi ◽  
Mi-Jin Kim ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Nuclear Receptor ◽  
Fibroblast Growth Factor 21 ◽  
Orphan Nuclear Receptor ◽  
Fibroblast Growth ◽  
Cultured Hepatocytes ◽  
Fgf21 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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