scholarly journals GCN2 is required to increase fibroblast growth factor 21 and maintain hepatic triglyceride homeostasis during asparaginase treatment

2015 ◽  
Vol 308 (4) ◽  
pp. E283-E293 ◽  
Author(s):  
Gabriel J. Wilson ◽  
Brittany A. Lennox ◽  
Pengxiang She ◽  
Emily T. Mirek ◽  
Rana J. T. Al Baghdadi ◽  
...  
Keyword(s):  
Growth Factor ◽  
Mrna Expression ◽  
Fibroblast Growth Factor ◽  
Liver Dysfunction ◽  
Antioxidant Defenses ◽  
Initiation Factor ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Hepatic Lipid ◽  
Hepatic Expression

The antileukemic agent asparaginase triggers the amino acid response (AAR) in the liver by activating the eukaryotic initiation factor 2 (eIF2) kinase general control nonderepressible 2 (GCN2). To explore the mechanism by which AAR induction is necessary to mitigate hepatic lipid accumulation and prevent liver dysfunction during continued asparaginase treatment, wild-type and Gcn2 null mice were injected once daily with asparaginase or phosphate buffered saline for up to 14 days. Asparaginase induced mRNA expression of multiple AAR genes and greatly increased circulating concentrations of the metabolic hormone fibroblast growth factor 21 (FGF21) independent of food intake. Loss of Gcn2 precluded mRNA expression and circulating levels of FGF21 and blocked mRNA expression of multiple genes regulating lipid synthesis and metabolism including Fas, Ppara, Pparg, Acadm, and Scd1 in both liver and white adipose tissue. Furthermore, rates of triglyceride export and protein expression of apolipoproteinB-100 were significantly reduced in the livers of Gcn2 null mice treated with asparaginase, providing a mechanistic basis for the increase in hepatic lipid content. Loss of AAR-regulated antioxidant defenses in Gcn2 null livers was signified by reduced Gpx1 gene expression alongside increased lipid peroxidation. Substantial reductions in antithrombin III hepatic expression and activity in the blood of asparaginase-treated Gcn2 null mice indicated liver dysfunction. These results suggest that the ability of the liver to adapt to prolonged asparaginase treatment is influenced by GCN2-directed regulation of FGF21 and oxidative defenses, which, when lost, corresponds with maladaptive effects on lipid metabolism and hemostasis.

scholarly journals Effect of Fibroblast Growth Factor 21 on the Expression of TLR4 and BAMBI Genes in Cholesterol-Treated Human Hepatic Stellate Cells

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Elham Shakerian ◽  
Narges Mohammad Taghvaei ◽  
Zohre Askari ◽  
Reza Afarin
Keyword(s):  
Growth Factor ◽  
Mrna Expression ◽  
Fibroblast Growth Factor ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Fibroblast Growth Factor 21 ◽  
Control Group ◽  
Type I ◽  
Fibroblast Growth ◽  
Human Hscs

Background: Activated hepatic stellate cells (HSCs) are the primary mediators in the progression of hepatic fibrosis. The activation of toll-like receptor 4 (TLR4) signaling leads to the downregulation of the transmembrane inhibitory transforming growth factor-beta (TGF-β) pseudoreceptor BMP and activin membrane-bound inhibitor (BAMBI) on HSCs. Fibroblast growth factor 21 (FGF21) is a natural secretory protein in the body with effects, such as the reduction of fat accumulation and oxidation of lipids; however; no study has investigated FGF21 ability to prevent the progression of liver fibrosis. Objectives: This study aimed to examine the beneficial effects of FGF21 to reduce cholesterol-activated human HSCs. Methods: The human HSCs were incubated in media containing different concentrations of cholesterol, including 25, 50, 75, 100, 125, and 150 μM, for 24 h and then incubated with FGF21 for 24 h. Total ribonucleic acids were extracted and reversely transcribed into complementary deoxyribonucleic acid. A quantitative real-time polymerase chain reaction was performed in this study. Results: The results showed that the messenger ribonucleic acid (mRNA) expression of TGF-β, collagen, type I, alpha 1 (collagen1α), and TLR4 genes increased significantly in the presence of cholesterol (75 and 100 μM), compared to that of the control group (* P < 0.05, ** P < 0.01, and *** P < 0.001); nevertheless, the mRNA expression of the BAMBI gene significantly reduced, compared to that of the control group (* P < 0.05). The FGF21 significantly reduced the mRNA expression of TGF-β, collagen1α, and TLR4 genes (# P < 0.05). The mRNA expression of the BAMBI gene significantly increased with FGF21 (# P < 0.05). Conclusions: It was concluded that the treatment with FGF21 reduces the cholesterol-activated HSCs by decreasing the mRNA expression of the TLR4, TGF-β, and collagen1α genes and increasing the mRNA expression of the BAMBI gene.

scholarly journals Activation of the Farnesoid X Receptor Induces Hepatic Expression and Secretion of Fibroblast Growth Factor 21

2012 ◽  
Vol 287 (30) ◽  
pp. 25123-25138 ◽  
Author(s):  
Holly A. Cyphert ◽  
Xuemei Ge ◽  
Alison B. Kohan ◽  
Lisa M. Salati ◽  
Yanqiao Zhang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Farnesoid X Receptor ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Hepatic Expression

scholarly journals Increased Circulating and Epicardial Adipose Tissue mRNA Expression of Fibroblast Growth Factor-21 After Cardiac Surgery: Possible Role in Postoperative Inflammatory Response and Insulin Resistance

2011 ◽  
pp. 757-767 ◽  
Author(s):  
T. KOTULÁK ◽  
J. DRÁPALOVÁ ◽  
P. KOPECKÝ ◽  
Z. LACINOVÁ ◽  
P. KRAMÁŘ ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Cardiac Surgery ◽  
Growth Factor ◽  
Mrna Expression ◽  
Fibroblast Growth Factor ◽  
Serum Glucose ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Baseline Serum

We studied the changes in serum fibroblast growth factor-21 (FGF-21) concentrations, its mRNA, and protein expression in skeletal muscle and adipose tissue of 15 patients undergoing cardiac surgery. Blood samples were obtained: prior to initiation of anesthesia, prior to the start of extracorporeal circulation, upon completion of the surgery, and 6, 24, 48, and 96 hours after the end of the surgery. Tissue sampling was performed at the start and end of surgery. The mean baseline serum FGF-21 concentration was 63.1 (43.03-113.95) pg/ml and it increased during surgery with peak 6 hours after its end [385.5 (274.55-761.65) pg/ml, p<0.001], and returned to baseline value [41.4 (29.15-142.83) pg/ml] 96 hours after the end of the surgery. Serum glucose, insulin, CRP, IL-6, IL-8, MCP-1, and TNF-alpha concentrations significantly increased during the surgery. Baseline FGF-21 mRNA expression in skeletal muscle was higher than in both adipose tissue depots and it was not affected by the surgery. Epicardial fat FGF-21 mRNA increased after surgery. Muscle FGF-21 mRNA positively correlated with blood glucose levels at the end of the surgery. Our data suggest a possible role of FGF-21 in the regulation of glucose metabolism and insulin sensitivity in surgery-related stress.

scholarly journals Hepatic Fibroblast Growth Factor 21 Is Regulated by PPARα and Is a Key Mediator of Hepatic Lipid Metabolism in Ketotic States

2007 ◽  
Vol 5 (6) ◽  
pp. 426-437 ◽  
Author(s):  
Michael K. Badman ◽  
Pavlos Pissios ◽  
Adam R. Kennedy ◽  
George Koukos ◽  
Jeffrey S. Flier ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Hepatic Lipid Metabolism ◽  
Hepatic Lipid

scholarly journals Dual effects of fibroblast growth factor 21 on hepatic energy metabolism

2015 ◽  
Vol 227 (1) ◽  
pp. 37-47 ◽  
Author(s):  
Ricardo J Samms ◽  
Michelle Murphy ◽  
Maxine J Fowler ◽  
Scott Cooper ◽  
Paul Emmerson ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Lipid Content ◽  
Negative Regulator ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Hepatic Lipid ◽  
Siberian Hamsters ◽  
Hepatic Lipid Content

The aim of this study was to investigate the mechanisms by which fibroblast growth factor 21 (FGF21) affects hepatic integration of carbohydrate and fat metabolism in Siberian hamsters, a natural model of adiposity. Twelve aged matched adult male Siberian hamsters maintained in their long-day fat state since birth were randomly assigned to one of two treatment groups and were continuously infused with either vehicle (saline;n=6) or recombinant human FGF21 protein (1 mg/kg per day;n=6) for 14 days. FGF21 administration caused a 40% suppression (P<0.05) of hepatic pyruvate dehydrogenase complex (PDC), the rate-limiting step in glucose oxidation, a 34% decrease (P<0.05) in hepatic acetylcarnitine accumulation, an index of reduced PDC flux, a 35% increase (P<0.05) in long-chain acylcarnitine content (an index of flux through β-oxidation) and a 47% reduction (P<0.05) in hepatic lipid content. These effects were underpinned by increased protein abundance of PD kinase-4 (PDK4, a negative regulator of PDC), the phosphorylated (inhibited) form of acetyl-CoA carboxylase (ACC, a negative regulator of delivery of fatty acids into the mitochondria) and the transcriptional co-regulators of energy metabolism peroxisome proliferator activated receptor gamma co-activator alpha (PGC1α) and sirtuin-1. These findings provide novel mechanistic basis to support the notion that FGF21 exerts profound metabolic benefits in the liver by modulating nutrient flux through both carbohydrate (mediated by a PDK4-mediated suppression of PDC activity) and fat (mediated by deactivation of ACC) metabolism, and therefore may be an attractive target for protection from increased hepatic lipid content and insulin resistance that frequently accompany obesity and diabetes.

scholarly journals Thyroid Hormone Regulates Hepatic Expression of Fibroblast Growth Factor 21 in aPPARα-dependent Manner

2010 ◽  
Vol 285 (19) ◽  
pp. 14078-14082 ◽  
Author(s):  
Andrew C. Adams ◽  
Inna Astapova ◽  
ffolliott M. Fisher ◽  
Michael K. Badman ◽  
Katherine E. Kurgansky ◽  
...  
Keyword(s):  
Growth Factor ◽  
Thyroid Hormone ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 21 ◽  
Dependent Manner ◽  
Fibroblast Growth ◽  
Hepatic Expression

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

Endocrinology ◽  
2011 ◽  
Vol 152 (8) ◽  
pp. 2996-3004 ◽  
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.

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

Endocrinology ◽  
2012 ◽  
Vol 153 (2) ◽  
pp. 750-758 ◽  
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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