成纤维细胞生长因子21:参与代谢调节的细胞因子

成纤维细胞生长因子21(FGF21)作为新近发现的内源性调节物质代谢因子,可由人体两大内分泌器官肝脏及骨骼肌分泌,其在调节代谢性疾病方面的生理作用近年来被医学界密切关注.大量研究发现FGF21可增加能量消耗、降低血浆与肝脏甘油三脂及低密度脂蛋白水平;调节葡萄糖代谢,发挥增强脂肪细胞摄取葡萄糖能力、降低血糖及抑制胰高血糖素分泌的作用.在临床2型糖尿病及非酒精性脂肪肝患者血浆中FGF21水平与对照组的显著差异具有统计学意义,且在控制其它因素后,其与病情的预后显著相关.而对于心血管病患者,FGF21可能通过其各项生理作用,拮抗心肌细胞凋亡及增强心肌抗氧化能力,一定程度上延缓心血管疾病的发生发展,但FGF21上述调节代谢相关性疾病的生理作用机制及途径目前尚不完全明确.本文简述FGF21的生物学特性及在代谢性疾病中的研究进展.     

Conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor

FGFs 19, 21, and 23 are hormones that regulate in a Klotho co-receptor-dependent fashion major metabolic processes such as glucose and lipid metabolism (FGF21) and phosphate and vitamin D homeostasis (FGF23). The role of heparan sulfate glycosaminoglycan in the formation of the cell surface signaling complex of endocrine FGFs has remained unclear. Here we show that heparan sulfate is not a component of the signal transduction unit of FGF19 and FGF23. In support of our model, we convert a paracrine FGF into an endocrine ligand by diminishing heparan sulfate-binding affinity of the paracrine FGF and substituting its C-terminal tail for that of an endocrine FGF containing the Klotho co-receptor-binding site to home the ligand into the target tissue. In addition to serving as a proof of concept, the ligand conversion provides a novel strategy for engineering endocrine FGF-like molecules for the treatment of metabolic disorders, including global epidemics such as type 2 diabetes and obesity.     

Passive heat loading links lipolysis and regulation of fibroblast growth factor-21 in humans

There is relativley little information on the serum biomarkers of heat stress. Therefore, the goal of this study was to verify the effect of passive heat loading (PHL) on the expression of fibroblast growth factor-21 (FGF21) and free fatty acids (FFAs). Four PHL protocols based on intensity (39 °C vs. 43 °C, leg immersion, 30 min) and type (leg vs. half immersion, 42 °C, 30 min) were used. Each protocol was applied on a 2 day cycle to 12 healthy adult males (age, 22.4±2.9 years; height, 174.1±4.6 cm; weight, 71.3±5.6 kg; body mass index, 23.1±3.0). The subjects were categorized into two groups according to the study design (randomized, with a parallel trial). Body temperature, FGF21 and FFAs were determined prior to PHL, immediately and 60 min after PHL. Body temperature was significant higher (43 °C) than the 39 °C measured under identical PHL type (leg immersion). PHL was effective for the expression of FGF21 and for lipolysis. The quantitative levels of FGF21 and FFA increased with increasing temperature (39 °C<42 °C<43 °C). A significant difference in the quantitative levels of FGF21 and FFAs was also evident based on the type of PHL (leg<half immersion) even when PHL was applied at the same temperature (42 °C). In conclusion, PHL was effective for expressing FGF21 and for lipolysis. Therefore, PHL may be expected to help in the reduction of body fat. Additionally, when the identical type (leg immersion) of PHL is applied, a loading temperature of 43 °C is more effective for expressing FGF21 and for lipolysis than temperatures of 39 °C and 42 °C, and half immersion is more effective than leg immersion at 42 °C.     

Identification of a second Klotho interaction site in the C terminus of FGF23

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碱性成纤维细胞生长因子(bFGF)相关结合蛋白

有四种不同类型的细胞表面或细胞外基质中的蛋白质分子在结合碱性成纤维细胞生长因子 (bFGF)、辅助其发挥生物功能活性方面起着重要的作用。它们是 :(1)细胞膜上的具有酪氨酸激酶活性的FGF受体家族 (FGFRs) ;(2 )细胞外基质中的硫酸乙酰肝素蛋白多糖家族 (HSPGs) ;(3)细胞内富含半胱氨酸的FGF受体 (CFR) ;(4)分泌型的FGF结合蛋白 (FGF BP)。本文试图从它们在bFGF生物功能发挥中可能起到的作用对它们进行简单综述。     

Phosphate toxicity and tumorigenesis

In this article, we briefly summarized evidence that cellular phosphate burden from phosphate toxicity is a pathophysiological determinant of cancer cell growth. Tumor cells express more phosphate cotransporters and store more inorganic phosphate than normal cells, and dysregulated phosphate homeostasis is associated with the genesis of various human tumors. High dietary phosphate consumption causes the growth of lung and skin tumors in experimental animal models. Additional studies show that excessive phosphate burden induces growth-promoting cell signaling, stimulates neovascularization, and is associated with chromosome instability and metastasis. Studies have also shown phosphate is a mitogenic factor that affects various tumor cell growth. Among epidemiological evidence linking phosphate and tumor formation, the Health Professionals Follow-Up Study found that high dietary phosphate levels were independently associated with lethal and high-grade prostate cancer. Further research is needed to determine how excessive dietary phosphate consumption influences initiation and promotion of tumorigenesis, and to elucidate prognostic benefits of reducing phosphate burden to decrease tumor cell growth and delay metastatic progression. The results of such studies could provide the basis for therapeutic modulation of phosphate metabolism for improved patient outcome.     

Functions of fibroblast growth factors in vertebrate development

Fibroblast growth factors (FGFs) are a class of secreted polypeptide ligands which mediate diverse cellular responses during embryonic, fetal, and postnatal vertebrate development. The purposes of this review are to provide a condensed overview of FGFs and their receptors, to catalog and categorize the functions of FGFs in vertebrate development, to present recent discoveries relating to the interplay of FGFs with other secreted ligands in the control of tissue growth and patterning, and to discuss several potential directions for future research in the field.     

Intracellular partners of fibroblast growth factors 1 and 2 - implications for functions

Fibroblast growth factors 1 and 2 (FGF1 and FGF2) are mainly considered as ligands of surface receptors through which they regulate a broad spectrum of biological processes. They are secreted in non-canonical way and, unlike other growth factors, they are able to translocate from the endosome to the cell interior. These unique features, as well as the role of the intracellular pool of FGF1 and FGF2, are far from being fully understood. An increasing number of reports address this problem, focusing on the intracellular interactions of FGF1 and 2. Here, we summarize the current state of knowledge of the FGF1 and FGF2 binding partners inside the cell and the possible role of these interactions. The partner proteins are grouped according to their function, including proteins involved in secretion, cell signaling, nucleocytoplasmic transport, binding and processing of nucleic acids, ATP binding, and cytoskeleton assembly. An in-depth analysis of the network of these binding partners could indicate novel, non-classical functions of FGF1 and FGF2 and uncover an additional level of a fine control of the well-known FGF-regulated cellular processes.     

The cooperation of FGF receptor and Klotho is involved in excretory canal development and regulation of metabolic homeostasis in Caenorhabditis elegans

FGFs have traditionally been associated with cell proliferation, morphogenesis, and development; yet, a subfamily of FGFs (FGF19, -21, and -23) functions as hormones to regulate glucose, lipid, phosphate, and vitamin D metabolism with impact on energy balance and aging. In mammals, Klotho and beta-Klotho are type 1 transmembrane proteins that function as obligatory co-factors for endocrine FGFs to bind to their cognate FGF receptors (FGFRs). Mutations in Klotho/beta-Klotho or fgf19, -21, or -23 are associated with a number of human diseases, including autosomal dominant hypophosphatemic rickets, premature aging disorders, and diabetes. The Caenorhabditis elegans genome contains two paralogues of Klotho/beta-Klotho, klo-1, and klo-2. klo-1 is expressed in the C. elegans excretory canal, which is structurally and functionally paralogous to the vertebrate kidney. KLO-1 associates with EGL-15/FGFR, suggesting a role for KLO-1 in the fluid homeostasis phenotype described previously for egl-15/fgfr mutants. Altered levels of EGL-15/FGFR signaling lead to defects in excretory canal development and function in C. elegans. These results suggest an evolutionarily conserved function for the FGFR-Klotho complex in the development of excretory organs such as the mammalian kidney and the worm excretory canal. These results also suggest an evolutionarily conserved function for the FGFR-Klotho axis in metabolic regulation.     

Discovery of 1,2,3-triazole-based fibroblast growth factor receptor modulators

To avoid production of a phospholipidosis-inducing metabolite, we replaced the amide structure of SUN13837 (1) with a 1,2,3-triazole. The resulting 1,2,3-triazole analog of 1 (compound 2) displayed greater neuroprotective activity than 1. Structural modification of 2 yielded compound 10, which showed improved neuroprotective activity and negligible mechanism-based inactivation against CYP3A4. In addition, installation of a methyl group at the 5-position of 1,2,3-triazole of 10 significantly boosted the neuroprotective activity. These 1,2,3-triazole derivatives displayed reduced phospholipidosis risk, sufficient systemic exposure, and high central nervous system penetration, and therefore may be potentially useful agents for the treatment of neurodegenerative diseases.     

Role of fibroblast growth factors as inducing agents in early embryonic development

To assess the potential role of a molecule in development we need to know three things: 1) what are the biological activities of the molecule, 2) what is its expression pattern, and 3) what are the consequences of removing it from the embryo? In the case of the FGF family in Xenopus embryos we have quite a lot of information about all three questions. Most members of the family can induce mesoderm from isolated animal caps, thus mimicking the natural “ventral vegetal” inducing signal operative in the blastula. This activity can be exerted on isolated, disaggregated cells and does not involve a change in division rate. When overexpressed from injected mRNA, the activity of FGFs depends largely on whether or not they possess a signal sequence, showing the importance of secretion in the inductive process. In addition to the mesoderm-inducing activity, there are effects of overexpression on whole embryos which lead to a suppression of anterior structures. Three types of FGF have so far been cloned from Xenopus: direct homologs of each of the mammalian types FGF-2 and FGF-3, and eFGF (“embryonic FGF”), which is equidistant in sequence from mammalian FGF-4 and FGF-6. Attempts to find homologs of mammalian FGF-5 and FGF-7 in Xenopus have proved unsuccessful. All three types of Xenopus FGF are expressed in early development. FGF-2 and eFGF are present in the oocyte and fertilized egg, and are thus both available at the time of mesoderm induction. FGF-3 and eFGF are both expressed from the embryonic genome during gastrulation and concentrated in the forming mesoderm. FGF-2 is expressed from the embryonic genome during neurulation in the brain, and a little later in the branchial arch mesenchyme and in the forming myotomes. These expression patterns suggest that there are several functions for the FGFs. The most successful strategy for inhibition of the FGF system has been the use of a dominant negative receptor construct introduced by Kirschner and colleagues. Overexpression of this construct can abolish the FGF responsiveness of animal caps. In whole embryos, the absence of FGF signaling causes a reduction, although not a total ablation, of mesoderm formation. There is also a severe effect on axis formation in which formation of the posterior parts is reduced consequent on an inhibition of invagination and elongation of the dorsal mesoderm. Thus, the present evidence suggests that the FGF system contributes to, although is not solely responsible for, mesoderm induction in vivo. It is also necessary for normal gastrulation movements, particularly in the dorsal mesoderm, and is likely to have several later functions, particularly in development of the central nervous system and the myotomes. © 1994 Wiley-Liss, Inc.     

FGF23, alpha-Klotho and vitamin D mediated calcium-phosphate metabolism in haemodialysis patients

BackgroundKlotho is a prote˝in that acts as a co-receptor for FGF23. FGF23-Klotho axis has great importance regarding the regulation of mineral metabolism by kidneys. In this study, we analysed FGF23, Klotho, 1,25-dihydroxyvitamin D3, 25-hydroxyvitamin D, parathormone, Calcium and Phosphate levels of haemodialysis patients in order to investigate the nature of the mineral metabolism disruption in chronic kidney diseases.MethodsSixty haemodialysis patients and 34 healthy controls were included in the study. Serum iFGF, cFGF, and soluble Klotho were analysed using ELISA kits. Moreover, 1,25-dihydroxyvitamin D3 was determined using LCMS/MS. Calcium, phosphate, iPTH and 25-hydroxyvitamin D were measured using autoanalyzers.ResultsIn haemodialysis patients, iFGF23, cFGF23, iPTH and P levels were significantly higher, and 1,25-dihydroxyvitamin D3, Klotho and Ca levels were significantly lower compared with the control group. There was no significant difference in the 25-hydroxyvitamin D levels.ConclusionsOur study showed that lack of sufficient amounts of Klotho is crucial for mineral metabolism disruptions seen as a complication of chronic kidney diseases. Despite the high levels of the hormone, FGF23 is unable to accomplish its function properly, likely due to deteriorated kidney function in haemodialysis patients.     

产油微生物油脂生物合成与代谢调控研究进展

自然界中少量微生物在适宜条件下产生并贮存质量超过其细胞干重 2 0 %的油脂 ,具有这种表型的菌种称为产油微生物。产油微生物利用可再生资源 ,得到的微生物油脂与植物油脂具有相似的脂肪酸组成 ,有的还含有丰富的多不饱和脂肪酸 ,具有广阔开发应用前景。简要介绍了产油微生物的种类和代谢特点 ,较详细地阐述了微生物产油机制和代谢调控途径的最新研究进展 ,并对微生物油脂研究的未来发展方向提出了初步见解     

Preclinical pharmacokinetic characterization of an adipose tissue-targeting monoclonal antibody in obese and non-obese animals

Target receptor levels can influence pharmacokinetics (PK) or pharmacodynamics (PD) of monoclonal antibodies (mAbs), and can affect drug development of this class of molecules. We generated an effector-less humanized bispecific antibody that selectively activates fibroblast growth factor receptor (FGFR)1 and βKlotho receptor, a FGF21 receptor complex highly expressed in both white and brown adipocytes. The molecule shows cross-species binding with comparable equilibrium binding affinity (Kd) for human, cynomolgus monkey, and mouse FGFR1/βKlotho. To understand the PK/PD relationship in non-obese and obese animals, we evaluated the adipose tissue distribution of the antibody, serum exposures, and an associated PD marker (high-molecular-weight adiponectin), in both non-obese and obese mice and monkeys. Antibody uptake into fat tissue was found to be higher on a per gram basis in non-obese animals compared to obese animals. Since obesity has been reported to be associated with reduced expression of FGFR1 and βKlotho receptor in white adipose tissues in mice, our results suggest that the distribution in adipose tissues was influenced by target expression levels. Even so, the overall dose-normalized serum exposures were comparable between non-obese and obese mice and monkeys, suggesting that adipose tissue uptake plays a limited role in overall systemic PK determination. It remains to be determined if and how obesity and receptor expression in humans influence the PK and PD profile of this novel therapeutic candidate.     

Ribosome stalling is a signal for metabolic regulation by the ribotoxic stress response

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Klotho and aging

The klotho gene encodes a single-pass transmembrane protein that forms a complex with multiple fibroblast growth factor (FGF) receptors and functions as an obligatory co-receptor for FGF23, a bone-derived hormone that induces negative phosphate balance. Defects in either Klotho or Fgf23 gene expression cause not only phosphate retention but also a premature-aging syndrome in mice, unveiling a potential link between phosphate metabolism and aging. In addition, the extracellular domain of Klotho protein is clipped on the cell surface and secreted into blood stream, potentially functioning as an endocrine factor. The secreted Klotho protein has a putative sialidase activity that modifies glycans on the cell surface, which may explain the ability of secreted Klotho protein to regulate activity of multiple ion channels and growth factors including insulin, IGF-1, and Wnt. Secreted Klotho protein also protects cells and tissues from oxidative stress through a mechanism yet to be identified. Thus, the transmembrane and secreted forms of Klotho protein have distinct functions, which may collectively affect aging processes in mammals.     

Glycogen synthase kinase 3 controls endochondral bone development: contribution of fibroblast growth factor 18

Glycogen synthase kinase 3 (GSK3) inhibits signaling pathways that are essential for bone development. To study the requirement for GSK activity during endochondral bone development, we inhibited GSK3 in cultured metatarsal bones with pharmacological antagonists. Interestingly, we find that inhibition of GSK3 strongly repressed chondrocyte and perichondrial osteoblast differentiation. Moreover, chondrocyte proliferation was inhibited, whereas perichondrial cell proliferation was stimulated. These results mirror the effects of fibroblast growth factor signaling (FGF), suggesting the FGF expression is induced. Indeed, we showed that (1) FGF18 expression is stimulated following inhibition of GSK3 and (2) GSK3 regulates FGF18 expression through the control of beta-catenin levels. Stimulation of cultured metatarsal with FGF18 had similar effects on the differentiation and proliferation of chondrocytes and perichondrial cells as GSK3 repression. This suggests that the regulation of FGF18 expression is a major function of GSK3 during endochondral bone development. Consistent with this, we showed that the effect of GSK3 inhibition on chondrocyte proliferation is repressed in tissues lacking a receptor for FGF18, FGF receptor 3.     

Serum concentrations of fibroblast growth factor 21 are elevated in patients with congenital or acquired lipodystrophy

ObjectivePatients with lipodystrophy (LD) suffer from loss of subcutaneous adipose tissue accompanied by dysregulation of several adipocyte-secreted factors. However, regulation of adipocyte-expressed fibroblast growth factor (FGF) 21 which acts in an insulin-mimetic, lipid-lowering, and anti-atherogenic manner has not been investigated in non-human immunodeficiency virus (HIV) LD.Material and methodsCirculating serum FGF21 levels were quantified in 37 patients with non-HIV LD and 37 controls matched for age, gender, and body mass index. Moreover, FGF21 plasma levels and mRNA expression were measured in LD mice and control animals. Additionally, serum FGF21 levels were assessed in 10 LD patients before and during metreleptin therapy.ResultsMedian FGF21 serum concentrations were significantly higher in LD patients (381.2 ng/l) as compared to the control group (231.2 ng/l; p = 0.023). There was an independent and positive association between circulating FGF21 and serum triglycerides (TG), as well as fibrate treatment, in multiple linear regression analysis. LD mice showed significantly upregulated FGF21 plasma levels (4.5-fold), as well as mRNA expression in various adipose tissue depots and liver as compared to controls (p < 0.05). Metreleptin treatment did not significantly alter circulating FGF21 levels in human subjects.ConclusionsSerum concentrations of FGF21 are elevated in patients with non-HIV LD with adipose tissue and liver being potential sources of increased production. TG and fibrate treatment are independent positive predictors of circulating FGF21.