scholarly journals Conjugated linoleic acid induces hepatic expression of fibroblast growth factor 21 through PPAR-α

2011 ◽  
Vol 107 (4) ◽  
pp. 461-465 ◽  
Author(s):  
Jie Yu ◽  
Bing Yu ◽  
Honglin Jiang ◽  
Daiwen Chen
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 21 ◽  
Dependent Manner ◽  
Fibroblast Growth ◽  
Hepatic Expression ◽  
Affinity Ligand ◽  
Glucose Homoeostasis ◽  
Soya Oil ◽  
Fgf21 Expression

Fibroblast growth factor 21 (FGF21) is a PPAR-α-regulated metabolic regulator that plays critical roles in glucose homoeostasis, lipid metabolism, insulin sensitivity and obesity. Conjugated linoleic acids (CLA), especially trans-10 (t-10), cis-12 (c-12), have shown anti-obesity properties. In addition, CLA is reported as a high-affinity ligand and activator of PPAR-α. This raises the possibility that FGF21 might be involved in the anti-obesity effect of CLA. In the present study, we tested the hypothesis that FGF21 expression in the liver could be induced by t-10, c-12-CLA through PPAR-α. HepG2 cells were treated with 100 μm-bovine serum albumin, 10 μm-t-10, c-12-CLA or 100 μm-t-10, c-12-CLA for 8 h. A total of ten adult C57BL/6J mice were fed with the diets containing 1 % soya oil or t-10, c-12-CLA for 5 d. t-10, c-12-CLA stimulated hepatic FGF21 mRNA abundance as determined by real-time RT-PCR. t-10, c-12-CLA also increased serum FGF21 concentrations as measured by an ELISA. Co-transfection analysis indicated that reporter gene expression from the mouse FGF21 promoter was induced by t-10, c-12-CLA in a PPAR-α-dependent manner. Taken together, these results suggest that t-10, c-12-CLA induces hepatic FGF21 expression through PPAR-α. This FGF21 and PPAR-α linkage may provide another potential explanation for the anti-obesity effect of t-10, c-12-CLA.

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 αKlotho attenuates cardiac hypertrophy and increases myocardial fibroblast growth factor 21 expression in uremic rats

2019 ◽  
Vol 245 (1) ◽  
pp. 66-78 ◽  
Author(s):  
Paulo Giovani de Albuquerque Suassuna ◽  
Paula Marocolo Cherem ◽  
Bárbara Bruna de Castro ◽  
Edgar Maquigussa ◽  
Marco Antonio Cenedeze ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Cardiac Remodeling ◽  
Untreated Group ◽  
Fibroblast Growth Factor 21 ◽  
Myocardial Remodeling ◽  
Fibroblast Growth ◽  
Uremic Cardiomyopathy ◽  
Cardioprotective Effects ◽  
Fgf21 Expression

In chronic kidney disease (CKD), evidence suggests that soluble αKlotho (sKlotho) has cardioprotective effects. Contrariwise, high circulating levels of fibroblast growth factor 23 (FGF23) are related to uremic cardiomyopathy development. Recently, it has been demonstrated that sKlotho can act as a soluble FGF23 co-receptor, allowing sKlotho to modulate FGF23 actions in the myocardium, leading to the activation of cardioprotective pathways. Fibroblast growth factor 21 (FGF21) is a cardiomyokine with sKlotho-like protective actions and has never been evaluated in uremic cardiomyopathy. Here, we aimed to evaluate whether recombinant αKlotho (rKlotho) replacement can attenuate cardiac remodeling in an established uremic cardiomyopathy, and to explore its impact on myocardial FGF21 expression. Forty-six male Wistar rats were divided into three groups: control, CKD-untreated, and CKD treated with rKlotho (CKD + KL). CKD was induced by 5/6 nephrectomy. From weeks 4–8, the control and CKD-untreated groups received vehicle, whereas the CKD + KL group received subcutaneous rKlotho replacement (0.01 mg/kg) every 48 h. Myocardial remodeling was evaluated by heart weight/tibia length (HW/TL) ratio, echocardiographic parameters, myocardial histomorphometry, and myocardial expression of β-myosin heavy chain (MHCβ), alpha smooth muscle actin (αSMA), transient receptor potential cation channel 6 (TRPC6), and FGF21. As expected, CKD animals had reduced levels of sKlotho and increased serum FGF23 levels. Compared to the control group, manifest myocardial remodeling was present in the CKD-untreated group, while it was attenuated in the CKD + KL group. Furthermore, cardiomyocyte diameter and interstitial fibrotic area were reduced in the CKD + KL group compared to the CKD-untreated group. Similarly, rKlotho replacement was associated with reduced myocardial expression of TRPC6, MHCβ, and αSMA and a higher expression of FGF21. rKlotho showed cardioprotective effects by attenuating myocardial remodeling and reducing TRPC6 expression. Interestingly, rKlotho replacement was also associated with increased myocardial FGF21 expression, suggesting that an interaction between the two cardioprotective pathways needs to be further explored. Impact statement This study aimed to evaluate whether rKlotho replacement can attenuate cardiac remodeling in a post-disease onset therapeutic reasoning and explore the impact on myocardial FGF21 expression. This study contributes significantly to the literature, as the therapeutic effects of rKlotho replacement and FGF21 myocardial expression have not been widely evaluated in a setting of uremic cardiomyopathy. For the first time, it has been demonstrated that subcutaneous rKlotho replacement may attenuate cardiac remodeling in established uremic cardiomyopathy and increase myocardial expression of FGF21, suggesting a correlation between αKlotho and myocardial FGF21 expression. The possibility of interaction between the αKlotho and FGF21 cardioprotective pathways needs to be further explored, but, if confirmed, would point to a therapeutic potential of FGF21 in uremic cardiomyopathy.

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

Cells ◽  
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.

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.

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 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 Bifidobacterium adolescentis Alleviates Liver Steatosis and Steatohepatitis by Increasing Fibroblast Growth Factor 21 Sensitivity

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaoxue Long ◽  
Dan Liu ◽  
Qiongmei Gao ◽  
Jiacheng Ni ◽  
Lingling Qian ◽  
...  
Keyword(s):  
Growth Factor ◽  
Gut Microbiota ◽  
Fibroblast Growth Factor ◽  
Liver Steatosis ◽  
Fibroblast Growth Factor 21 ◽  
Dependent Manner ◽  
Fibroblast Growth ◽  
Bifidobacterium Adolescentis ◽  
Alcoholic Fatty Liver ◽  
Response Test

The gut microbiota is a newly identified contributor to the development of non-alcoholic fatty liver disease (NAFLD). Previous studies of Bifidobacterium adolescentis (B. adolescentis), a species of Bifidobacterium that is common in the human intestinal tract, have demonstrated that it can alleviate liver steatosis and steatohepatitis. Fibroblast growth factor 21 (FGF21) has long been considered as a biomarker of NAFLD, and recent studies have shown the protective effect of FGF21 analogs on NAFLD. We wondered whether B. adolescentis treatment would alleviate NAFLD via the interaction with FGF21. To this end, male C57BL/6J mice on a choline-deficient high-fat diet (CDHFD) were treated with drinking water supplemented with B. adolescentis for 8 weeks, followed by the acute administration of recombinant mouse FGF21 protein (rmFGF21) to conduct the FGF21 response test. Consistent with previous studies, B. adolescentis supplementation reversed the CDHFD-induced liver steatosis and steatohepatitis. This was evaluated on the NAFLD activity score (NAS), reduced liver enzymes, and lipid accumulation. Further studies demonstrated that B. adolescentis supplementation preserved the gut barrier, reduced the gut microbiota-derived lipopolysaccharide (LPS), and inhibited the hepatic TLR4/NF-κB pathway. This was accompanied by the elevated expressions of the receptors of FGF21, fibroblast growth factor receptor 1 (FGFR1) and β-klotho (KLB), in the liver and the decreased expression of FGF21. The results of FGF21 response test showed that B. adolescentis supplementation alleviated the CDHFD-induced FGF21 resistance. In vivo experiments suggested that LPS could suppress the expression of FGF21 and KLB in a dose-dependent manner. Collectively, this study showed that B. adolescentis supplementation could alleviate NAFLD by increasing FGF21 sensitivity.

scholarly journals Fibroblast growth factor 21 in dairy cows: current knowledge and potential relevance

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Klaus Eder ◽  
Denise K. Gessner ◽  
Robert Ringseis
Keyword(s):  
Growth Factor ◽  
Energy Balance ◽  
Dairy Cows ◽  
Fibroblast Growth Factor ◽  
Negative Energy ◽  
Stress Conditions ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Fgf21 Expression

AbstractFibroblast growth factor 21 (FGF21) has been identified as an important regulator of carbohydrate and lipid metabolism, which plays an important role for metabolic regulation, particularly under conditions of energy deprivation or stress conditions. Dairy cows are subjected to a negative energy balance and various kinds of stress particularly during the periparturient phase and during early lactation. It has been shown that the plasma concentration of FGF21 in dairy cows is dramatically increased at parturition and remains high during the first weeks of lactation. This finding suggests that FGF21 might exert similar functions in dairy cows than in other species, such as mice or humans. However, the role of FGF21 in dairy cows has been less investigated so far. Following a brief summary of the previous findings about the function of FGF21 in humans and mice, the present review aims to present the current state of knowledge about the role of FGF21 in dairy cows. The first part of the review deals with the tissue localization of FGF21 and with conditions leading to an upregulation of FGF21 expression in the liver of dairy cows. In the second part, the influence of nutrition on FGF21 expression and the role of FGF21 for metabolic diseases in dairy cows is addressed. In the third part, findings of exogenous FGF21 application on metabolism in dairy cows are reported. Finally, the potential relevance of FGF21 in dairy cows is discussed. It is concluded that FGF21 might be of great importance for metabolic adaptation to negative energy balance and stress conditions in dairy cows. However, further studies are needed for a better understanding of the functions of FGF21 in dairy cows.

Sign in / Sign up

Export Citation Format

Share Document