scholarly journals Metformin Stimulates FGF21 Expression in Primary Hepatocytes

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Eva B. Nygaard ◽  
Sara G. Vienberg ◽  
Cathrine Ørskov ◽  
Harald S. Hansen ◽  
Birgitte Andersen
Keyword(s):  
Human Hepatocytes ◽  
Fibroblast Growth Factor 21 ◽  
Potent Inducer ◽  
Glucose And Lipid Metabolism ◽  
Compound C ◽  
Mrna And Protein Expression ◽  
Dose Dependent Increase ◽  
Fgf21 Expression

Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator of glucose and lipid metabolism; however, the exact mechanism of action and regulation of FGF21 is not fully understood. Metabolic status plays an important role in the regulation of FGF21, and we therefore examined whether metformin, an indirect AMPK-activator, regulates FGF21 expression in hepatocytes. FGF21 mRNA and protein expression were determined after incubation of primary cultured rat and human hepatocytes with metformin for 24 hours. To study the role of AMPK in the putative regulation of FGF21, hepatocytes were incubated with Compound C (an AMPK inhibitor) in the presence of metformin. A strong dose-dependent increase in FGF21 expression was observed in both rat and human hepatocytes treated with metformin. This effect was blocked by addition of the AMPK-inhibitor Compound C. The study shows that metformin is a potent inducer of hepatic FGF21 expression and that the effect of metformin seems to be mediated through AMPK activation. As FGF21 therapy normalizes blood glucose in animal models of type 2 diabetes, the induction of hepatic FGF21 by metformin might play an important role in metformin’s antidiabetic effect.

scholarly journals Increased FGF21 plasma levels in humans with sepsis and SIRS

2013 ◽  
Vol 2 (3) ◽  
pp. 146-153 ◽  
Author(s):  
Karim Gariani ◽  
Geneviève Drifte ◽  
Irène Dunn-Siegrist ◽  
Jérôme Pugin ◽  
François R Jornayvaz
Keyword(s):  
Plasma Levels ◽  
Plasma Concentrations ◽  
Apache Ii Score ◽  
Fibroblast Growth Factor 21 ◽  
Healthy Controls ◽  
Nonalcoholic Fatty Liver ◽  
Reactive Protein ◽  
Glucose And Lipid Metabolism

Fibroblast growth factor 21 (FGF21) is a key regulator in glucose and lipid metabolism and its plasma levels have been shown to be increased not only in humans in different situations such as type 2 diabetes, obesity, and nonalcoholic fatty liver disease but also in animal models of sepsis and pancreatitis. FGF21 is considered as a pharmacological candidate in conditions associated with insulin resistance. The aim of this study was to compare FGF21 plasma levels in patients with sepsis, in patients with systemic inflammatory response syndrome (SIRS), and in healthy controls. We measured FGF21 plasma concentrations in 22 patients with established sepsis, in 11 with SIRS, and in 12 healthy volunteers. Here, we show that FGF21 levels were significantly higher in plasma obtained from patients with sepsis and SIRS in comparison with healthy controls. Also, FGF21 levels were significantly higher in patients with sepsis than in those with noninfectious SIRS. FGF21 plasma levels measured at study entry correlated positively with the APACHE II score, but not with procalcitonin levels, nor with C-reactive protein, classical markers of sepsis. Plasma concentrations of FGF21 peaked near the onset of shock and rapidly decreased with clinical improvement. Taken together, these results indicate that circulating levels of FGF21 are increased in patients presenting with sepsis and SIRS, and suggest a role for FGF21 in inflammation. Further studies are needed to explore the potential role of FGF21 in sepsis as a potential therapeutic target.

Effect of curcumin on acidic pH-induced expression of IL-6 and IL-8 in human esophageal epithelial cells (HET-1A): role of PKC, MAPKs, and NF-κB

2009 ◽  
Vol 296 (2) ◽  
pp. G388-G398 ◽  
Author(s):  
Parvaneh Rafiee ◽  
Victoria M. Nelson ◽  
Sharon Manley ◽  
Michael Wellner ◽  
Martin Floer ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Mucosal Injury ◽  
Inhibitory Effect ◽  
Acidic Ph ◽  
Induced Expression ◽  
Potent Inducer ◽  
Mrna And Protein Expression ◽  
Esophageal Epithelial Cells ◽  
P38 Mapk Inhibitor

Human esophageal epithelial cells play a key role in esophageal inflammation in response to acidic pH during gastroesophageal reflux disease (GERD), increasing secretion of IL-6 and IL-8. The mechanisms underlying IL-6 and IL-8 expression and secretion in esophageal epithelial cells after acid stimulation are not well characterized. We investigated the role of PKC, MAPK, and NF-κB signaling pathways and transcriptional regulation of IL-6 and IL-8 expression in HET-1A cells exposed to acid. Exposure of HET-1A cells to pH 4.5 induced NF-κB activity and enhanced IL-6 and IL-8 secretion and mRNA and protein expression. Acid stimulation of HET-1A cells also resulted in activation of MAPKs and PKC (α and ε). Curcumin, as well as inhibitors of NF-κB (SN-50), PKC (chelerythrine), and p44/42 MAPK (PD-098059) abolished the acid-induced expression of IL-6 and IL-8. The JNK inhibitor SP-600125 blocked expression/secretion of IL-6 but only partially attenuated IL-8 expression. The p38 MAPK inhibitor SB-203580 did not inhibit IL-6 expression but exerted a stronger inhibitory effect on IL-8 expression. Together, these data demonstrate that 1) acid is a potent inducer of IL-6 and IL-8 production in HET-1A cells; 2) MAPK and PKC signaling play a key regulatory role in acid-mediated IL-6 and IL-8 expression via NF-κB activation; and 3) the anti-inflammatory plant compound curcumin inhibits esophageal activation in response to acid. Thus IL-6 and IL-8 expression by acid may contribute to the pathobiology of mucosal injury in GERD, and inhibition of the NF-κB/proinflammatory cytokine pathways may emerge as important therapeutic targets for treatment of esophageal inflammation.

scholarly journals Fibroblast growth factor 21: a regulator of metabolic disease and health span

2017 ◽  
Vol 313 (3) ◽  
pp. E292-E302 ◽  
Author(s):  
Ting Xie ◽  
Po Sing Leung
Keyword(s):  
Lipid Metabolism ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Metabolic Diseases ◽  
Scientific Basis ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Glucose And Lipid Metabolism ◽  
Care Guidelines

Fibroblast growth factor 21 (FGF21) is a potent endocrine regulator with physiological effects on glucose and lipid metabolism and thus garners much attention for its translational potential for the management of obesity and related metabolic syndromes. FGF21 is mainly expressed in several metabolically active tissue organs, such as the liver, adipose tissue, skeletal muscle, and pancreas, with profound effects and therapeutic relevance. Emerging experimental and clinical data point to the demonstrated metabolic benefits of FGF21, which include, but are not limited to, weight loss, glucose and lipid metabolism, and insulin sensitivity. In addition, FGF21 also acts directly through its coreceptor β-klotho in the brain to alter light-dark cycle activity. In this review, we critically appraise current advances in understanding the physiological actions of FGF21 and its role as a biomarker of various metabolic diseases, especially type 2 diabetes mellitus. We also discuss the potentially exciting role of FGF21 in improving our health and prolonging our life span. This information will provide a fuller understanding for further research into FGF21, as well as providing a scientific basis for potentially establishing health care guidelines for this promising molecule.

scholarly journals THE ROLE OF MYOKINES INTERSTITIAL INTERACTION AND REGULATION OF METABOLISM: A REVIEW OF LITERATURE

2016 ◽  
Vol 19 (1) ◽  
pp. 28-34
Author(s):  
T T Tsoriev ◽  
Zh E White ◽  
L Ya Rozhinskaya
Keyword(s):  
Skeletal Muscles ◽  
Metabolic Disorders ◽  
Visceral Obesity ◽  
Signal Pathways ◽  
Review Of Literature ◽  
Glucose And Lipid Metabolism ◽  
Regulation Of Metabolism ◽  
Skin Mucosa

Myokines are hormone-like acting molecules produced in skeletal muscles during and immediately after exercise. They affect both paracrine (inside the muscles themselves) and endocrine manner (in adipose tissue, liver, endothelium, skin, mucosa etc.) implementing different effects on target tissues, mainly through regulation of metabolic processes (such as glucose and lipid metabolism, growth and division of neurons and endothelial cells and others). The examination of myokines is of great interest for researchers of different medicine departments, particularly for endocrinologists, because of myokines’ involvement in pathogenesis of abdominal and visceral obesity, diabetes mellitus type 2 and cardiovascular diseases that are all the components of metabolic syndrome. The most important issue for clinicians is a possibility of future therapeutic implication of the myokine’s signal pathways in treatment of widespread metabolic disorders.

scholarly journals ATF4- and CHOP-Dependent Induction of FGF21 through Endoplasmic Reticulum Stress

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Xiao-shan Wan ◽  
Xiang-hong Lu ◽  
Ye-cheng Xiao ◽  
Yuan Lin ◽  
Hong Zhu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Transcriptional Activation ◽  
Metabolic Diseases ◽  
Human Subjects ◽  
Fibroblast Growth Factor 21 ◽  
Dependent Manner ◽  
Nonalcoholic Fatty Liver ◽  
Glucose And Lipid Metabolism ◽  
Fgf21 Expression

Fibroblast growth factor 21 (FGF21) is an important endogenous regulator involved in the regulation of glucose and lipid metabolism. FGF21 expression is strongly induced in animal and human subjects with metabolic diseases, but little is known about the molecular mechanism. Endoplasmic reticulum (ER) stress plays an essential role in metabolic homeostasis and is observed in numerous pathological processes, including type 2 diabetes, overweight, nonalcoholic fatty liver disease (NAFLD). In this study, we investigate the correlation between the expression of FGF21 and ER stress. We demonstrated that TG-induced ER stress directly regulated the expression and secretion of FGF21 in a dose- and time-dependent manner. FGF21 is the target gene for activating transcription factor 4 (ATF4) and CCAAT enhancer binding protein homologous protein (CHOP). Suppression of CHOP impaired the transcriptional activation of FGF21 by TG-induced ER stress in CHOP−/− mouse primary hepatocytes (MPH), and overexpression of ATF4 and CHOP resulted in FGF21 promoter activation to initiate the transcriptional programme. In mRNA stability assay, we indicated that ER stress increased the half-life of mRNA of FGF21 significantly. In conclusion, FGF21 expression is regulated by ER stress via ATF- and CHOP-dependent transcriptional mechanism and posttranscriptional mechanism, respectively.

scholarly journals Role of EDHF in type 2 diabetes-induced endothelial dysfunction

2008 ◽  
Vol 295 (5) ◽  
pp. H1982-H1988 ◽  
Author(s):  
Yoonjung Park ◽  
Stefano Capobianco ◽  
Xue Gao ◽  
John R. Falck ◽  
Kevin C. Dellsperger ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Dysfunction ◽  
Neutralizing Antibody ◽  
Prostaglandin Synthase ◽  
Mrna And Protein Expression ◽  
Synthase Inhibitor ◽  
Selective Blocker ◽  
Small Conductance

Endothelium-derived hyperpolarizing factor (EDHF) plays a crucial role in modulating vasomotor tone, especially in microvessels when nitric oxide-dependent control is compromised such as in diabetes. Epoxyeicosatrienoic acids (EETs), potassium ions (K+), and hydrogen peroxide (H2O2) are proposed as EDHFs. However, the identity (or identities) of EDHF-dependent endothelial dilators has not been clearly elucidated in diabetes. We assessed the mechanisms of EDHF-induced vasodilation in wild-type (WT, normal), db/db (advanced type 2 diabetic) mice, and db/db mice null for TNF (dbTNF−/dbTNF−). In db/db mice, EDHF-induced vasodilation [ACh-induced vasodilation in the presence of NG-nitro-l-arginine methyl ester (l-NAME, 10 μmol/l) and prostaglandin synthase inhibitor indomethacin (Indo, 10 μmol/l)] was diminished after the administration of catalase (an enzyme that selectively dismutates H2O2 to water and oxygen, 1,000 U/ml); administration of the combination of charybdotoxin (a nonselective blocker of intermediate-conductance Ca2+-activated K+ channels, 10 μmol/l) and apamin (a selective blocker of small-conductance Ca2+-activated K+ channels, 50 μmol/l) also attenuated EDHF-induced vasodilation, but the inhibition of EETs synthesis [14,15-epoxyeicosa-5(Z)-enoic acid; 10 μmol/l] did not alter EDHF-induced vasodilation. In WT controls, EDHF-dependent vasodilation was significantly diminished after an inhibition of K+ channel, EETs synthesis, or H2O2 production. Our molecular results indicate that mRNA and protein expression of interleukin-6 (IL-6) were greater in db/db versus WT and dbTNF−/dbTNF− mice, but neutralizing antibody to IL-6 (anti-IL-6; 0.28 mg·ml−1·kg−1 ip for 3 days) attenuated IL-6 expression in db/db mice. The incubation of the microvessels with IL-6 (5 ng/ml) induced endothelial dysfunction in the presence of l-NAME and Indo in WT mice, but anti-IL-6 restored ACh-induced vasodilation in the presence of l-NAME and Indo in db/db mice. In dbTNF−/dbTNF− mice, EDHF-induced vasodilation was greater and comparable with controls, but IL-6 decreased EDHF-mediated vasodilation. Our results indicate that EDHF compensates for diminished NO-dependent dilation in IL-6-induced endothelial dysfunction by the activation of H2O2 or a K+ channel in type 2 diabetes.

scholarly journals FGF21 facilitates autophagy in prostate cancer cells by inhibiting the PI3K–Akt–mTOR signaling pathway

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Han Dai ◽  
Wenjing Hu ◽  
Lianying Zhang ◽  
Feiyu Jiang ◽  
Xiongmin Mao ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Mammalian Target Of Rapamycin ◽  
Fibroblast Growth Factor 21 ◽  
Mtor Signaling Pathway ◽  
Lncap Cells ◽  
Phosphatidylinositol 3 Kinase ◽  
Glucose And Lipid Metabolism ◽  
Novel Target ◽  
Fgf21 Expression

AbstractFibroblast growth factor 21 (FGF21) plays an important role in regulating glucose and lipid metabolism, but its role in cancer is less well-studied. We aimed to investigate the action of FGF21 in the development of prostate cancer (PCa). Herein, we found that FGF21 expression was markedly downregulated in PCa tissues and cell lines. FGF21 inhibited the proliferation and clone formation of LNCaP cells (a PCa cell line) and promoted apoptosis. FGF21 also inhibited PCa cell migration and invasiveness. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that FGF21 was related to autophagy and the phosphatidylinositol 3-kinase–Akt kinase–mammalian target of rapamycin (PI3K–Akt–mTOR) pathway. Mechanistically, FGF21 promoted autophagy in LNCaP cells by inhibiting the PI3K–Akt–mTOR–70S6K pathway. In addition, FGF21 inhibited PCa tumorigenesis in vivo in nude mice. Altogether, our findings show that FGF21 inhibits PCa cell proliferation and promoted apoptosis in PCa cells through facilitated autophagy. Therefore, FGF21 might be a potential novel target in PCa therapy.

scholarly journals The Roles and Pharmacological Effects of FGF21 in Preventing Aging-Associated Metabolic Diseases

2021 ◽  
Vol 8 ◽  
Author(s):  
Junbin Yan ◽  
Yunmeng Nie ◽  
Jielu Cao ◽  
Minmin Luo ◽  
Maoxiang Yan ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Metabolic Diseases ◽  
Cellular Aging ◽  
Fibroblast Growth Factor 21 ◽  
Aging Effects ◽  
Dark Cloud ◽  
Alcoholic Fatty Liver ◽  
Glucose And Lipid Metabolism ◽  
Theoretical Support

With the continuous improvement of living standards but the lack of exercise, aging-associated metabolic diseases such as obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic fatty liver disease (NAFLD) are becoming a lingering dark cloud over society. Studies have found that metabolic disorders are near related to glucose, lipid metabolism, and cellular aging. Fibroblast growth factor 21 (FGF21), a member of the FGFs family, efficiently regulates the homeostasis of metabolism and cellular aging. By activating autophagy genes and improving inflammation, FGF21 indirectly delays cellular aging and directly exerts anti-aging effects by regulating aging genes. FGF21 can also regulate glucose and lipid metabolism by controlling metabolism-related genes, such as adipose triglyceride lipase (ATGL) and acetyl-CoA carboxylase (ACC1). Because FGF21 can regulate metabolism and cellular aging simultaneously, FGF21 analogs and FGF21 receptor agonists are gradually being valued and could become a treatment approach for aging-associated metabolic diseases. However, the mechanism by which FGF21 achieves curative effects is still not known. This review aims to interpret the interactive influence between FGF21, aging, and metabolic diseases and delineate the pharmacology of FGF21, providing theoretical support for further research on FGF21.

scholarly journals Gentiopicroside Ameliorates Glucose and Lipid Metabolism in T2DM by Activating PI3K/AKT Pathway Via FGFR1

2021 ◽  
Author(s):  
Zhanchi Xu ◽  
Zeyuan Lin ◽  
Jingran Zeng ◽  
Rui Chen ◽  
Chuting Li ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Glucose Metabolism ◽  
Hepg2 Cells ◽  
Growth Factor Receptor ◽  
Akt Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Glucose And Lipid Metabolism ◽  
Lipid Metabolism Disorders

Abstract Background: Abnormalities in lipid and glucose metabolism are are constantly occured in type 2 diabetes (T2DM). However, it can be ameliorated by gentiopicroside (GPS). Considering the key role of fibroblast growth factor receptor 1/phosphatidylinositol 3-kinase/protein kinase B (FGFR1/PI3K/AKT) pathway in T2DM, we explore the possible mechanism of GPS on lipid and glucose metabolism through its effects on FGFR1/PI3K/AKT pathway.Methods: Palmitic acid (PA)-induced HepG2 cells and a db/db mice were used to clarify the role and mechanism of polydatin on lipid and glucose metabolism.Results: GPS ameliorated glucose and lipid metabolism disorders in db/db mice and PA-induced HepG2 cells. Furthermore, GPS activated FGFR1/PI3K/AKT pathway including increased the protein expression of FGFR1 and promoted the phosphorylation of PI3K, AKT and FoxO1. Additionally, knockdown of FGFR1 reversed the activation of PI3K/AKT pathway by GPS.Conclusions: The present study demontrates that GPS ameliorates glucose and lipid metabolism disorders via activation of FGFR1/PI3K/AKT pathway.

scholarly journals ANGPTL8 in metabolic homeostasis: more friend than foe?

Open Biology ◽  
2021 ◽  
Vol 11 (9) ◽  
Author(s):  
Chang Guo ◽  
Chenxi Wang ◽  
Xia Deng ◽  
Jianqiang He ◽  
Ling Yang ◽  
...  
Keyword(s):  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Hepatic Glucose Production ◽  
Physiological Role ◽  
Glucose Production ◽  
Peripheral Tissues ◽  
Glucose And Lipid Metabolism ◽  
Hepatic Glucose

ANGPTL8 is an important cytokine, which is significantly increased in type 2 diabetes mellitus (T2DM), obesity and metabolic syndrome. Many studies have shown that ANGPTL8 can be used as a bio-marker of these metabolic disorders related diseases, and the baseline ANGPTL8 level has also been found to be positively correlated with retinopathy and all-cause mortality in patients with T2DM. This may be related to the inhibition of lipoprotein lipase activity and the reduction of circulating triglyceride (TG) clearance by ANGPTL8. Consistently, inhibition of ANGPTL8 seems to prevent or improve atherosclerosis. However, it is puzzling that ANGPTL8 seems to have a directing function for TG uptake in peripheral tissues; that is, ANGPTL8 specifically enhances the reserve and buffering function of white adipose tissue, which may alleviate the ectopic lipid accumulation to a certain extent. Furthermore, ANGPTL8 can improve insulin sensitivity and inhibit hepatic glucose production. These contradictory results lead to different opinions on the role of ANGPTL8 in metabolic disorders. In this paper, the correlation between ANGPTL8 and metabolic diseases, the regulation of ANGPTL8 and the physiological role of ANGPTL8 in the process of glucose and lipid metabolism were summarized, and the physiological/pathological significance of ANGPTL8 in the process of metabolic disorder was discussed.

Sign in / Sign up

Export Citation Format

Share Document