Neohesperidin Exerts Lipid-Regulating Effects in vitro and in vivo via Fibroblast Growth Factor 21 and AMP-Activated Protein Kinase/Sirtuin Type 1/Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1α Signaling Axis

Pharmacology ◽  
2017 ◽  
Vol 100 (3-4) ◽  
pp. 115-126 ◽  
Author(s):  
Haoshu Wu ◽  
Yunxi Liu ◽  
Xiaobing Chen ◽  
Difeng Zhu ◽  
Jian Ma ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor 21 ◽  
Peroxisome Proliferator ◽  
Fibroblast Growth ◽  
Peroxisome Proliferator Activated Receptor ◽  
Signaling Axis ◽  
Amp Activated Protein Kinase

scholarly journals Pemafibrate Prevents Retinal Pathological Neovascularization by Increasing FGF21 Level in a Murine Oxygen-Induced Retinopathy Model

2019 ◽  
Vol 20 (23) ◽  
pp. 5878 ◽  
Author(s):  
Yohei Tomita ◽  
Nobuhiro Ozawa ◽  
Yukihiro Miwa ◽  
Ayako Ishida ◽  
Masayuki Ohta ◽  
...  
Keyword(s):  
Growth Factor ◽  
Large Scale ◽  
Luciferase Assay ◽  
Fibroblast Growth Factor 21 ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Fatty Acid Binding ◽  
Pathological Angiogenesis ◽  
Oxygen Induced Retinopathy

Large-scale clinical trials, such as the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies, have shown that the administration of fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, suppresses the progression of diabetic retinopathy. In this paper, we reveal a therapeutic effect of a selective PPARα modulator (SPPARMα), pemafibrate, against pathological angiogenesis in murine models of retinopathy. Oxygen-induced retinopathy (OIR) was induced in C57BL/6J mice by exposure to 85% oxygen from postnatal day eight (P8) for 72 h. Vehicle, pemafibrate or fenofibrate was administrated by oral gavage from P12 to P16 daily. Administration of pemafibrate, but not fenofibrate, significantly reduced pathological angiogenesis in OIR. After oral pemafibrate administration, expression levels of downstream PPARα targets such as acyl-CoA oxidase 1 (Acox1), fatty acid binding protein 4 (Fabp4), and fibroblast growth factor 21 (Fgf21) were significantly increased in the liver but not in the retina. A significant increase in plasma FGF21 and reduced retinal hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor A (Vegfa) were also observed after this treatment. In an in vitro HIF-luciferase assay, a long-acting FGF21 analogue, but not pemafibrate, suppressed HIF activity. These data indicate that SPPARMα pemafibrate administration may prevent retinal pathological neovascularization by upregulating FGF21 in the liver.

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 miR-139 Functions as An Antioncomir to Repress Glioma Progression Through Targeting IGF-1 R, AMY-1, and PGC-1β

2016 ◽  
Vol 16 (4) ◽  
pp. 497-511 ◽  
Author(s):  
Hong Wang ◽  
Xi Yan ◽  
Li-Ya Ji ◽  
Xi-Tuan Ji ◽  
Ping Wang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Epigenetic Modification ◽  
Negative Control ◽  
Peroxisome Proliferator ◽  
Insulin Like Growth Factor ◽  
Peroxisome Proliferator Activated Receptor

Gliomas are the most common primary malignant brain tumor with poor prognosis, characterized by a highly heterogeneous cell population, extensive proliferation, and migration. A lot of molecular mechanisms regulate gliomas development and invasion, including abnormal expression of oncogenes and variation of epigenetic modification. MicroRNAs could affect cell growth and functions. Several reports have demonstrated that miR-139 plays multifunctions in kinds of solid tumors through different pathways. However, the antitumor mechanisms of this miR-139 are not unveiled in detail. In this study, we not only validated the low expression level of miR-139 in glioma tissues and cell lines but also detected the effect of miR-139 on modulating gliomas proliferation and invasion both in vitro and in vivo. We identified insulin-like growth factor 1 receptor, associate of Myc 1, and peroxisome proliferator-activated receptor γ coactivator 1β as direct targets of miR-139 and the levels of them were all inversely correlated with miR-139 in gliomas. Insulin like growth factor 1 receptor promoted gliomas invasion through Akt signaling and increased proliferation in the peroxisome proliferator-activated receptor γ coactivator 1β-dependent way. Associate of Myc 1 also facilitated gliomas progression by activating c-Myc pathway. Overexpression of the target genes could retrieve the antitumor function of miR-139, respectively, in different degrees. The nude mice transplantation tumor experiment displayed that glioma cells stably expressed miR-139 growth much slower in vivo than the negative control cells. Taken together, these findings suggested miR-139 acted as a favorable factor against gliomas progression and uncovered a novel regulatory mechanism, which may provide a new evidenced prognostic marker and therapeutic target for gliomas.

scholarly journals Glucagon and lipid interactions in the regulation of hepatic AMPK signaling and expression of PPARα and FGF21 transcripts in vivo

2010 ◽  
Vol 299 (4) ◽  
pp. E607-E614 ◽  
Author(s):  
Eric D. Berglund ◽  
Li Kang ◽  
Robert S. Lee-Young ◽  
Clinton M. Hasenour ◽  
Daniel G. Lustig ◽  
...  
Keyword(s):  
Whole Body ◽  
Fibroblast Growth Factor 21 ◽  
Peroxisome Proliferator ◽  
Glucagon Receptor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ampk Signaling ◽  
Downstream Target ◽  
Amp Activated Protein Kinase ◽  
Fgf21 Expression

Hepatic glucagon action increases in response to accelerated metabolic demands and is associated with increased whole body substrate availability, including circulating lipids. The hypothesis that increases in hepatic glucagon action stimulate AMP-activated protein kinase (AMPK) signaling and peroxisome proliferator-activated receptor-α (PPARα) and fibroblast growth factor 21 (FGF21) expression in a manner modulated by fatty acids was tested in vivo. Wild-type ( gcgr+/+) and glucagon receptor-null ( gcgr−/−) littermate mice were studied using an 18-h fast, exercise, and hyperglucagonemic-euglycemic clamps plus or minus increased circulating lipids. Fasting and exercise in gcgr+/+, but not gcgr−/− mice, increased hepatic phosphorylated AMPKα at threonine 172 (p-AMPKThr172) and PPARα and FGF21 mRNA. Clamp results in gcgr+/+ mice demonstrate that hyperlipidemia does not independently impact or modify glucagon-stimulated increases in hepatic AMP/ATP, p-AMPKThr172, or PPARα and FGF21 mRNA. It blunted glucagon-stimulated acetyl-CoA carboxylase phosphorylation, a downstream target of AMPK, and accentuated PPARα and FGF21 expression. All effects were absent in gcgr−/− mice. These findings demonstrate that glucagon exerts a critical regulatory role in liver to stimulate pathways linked to lipid metabolism in vivo and shows for the first time that effects of glucagon on PPARα and FGF21 expression are amplified by a physiological increase in circulating lipids.

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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