FGF19
Fibroblast growth factor 19 precursor (FGF-19) [UNQ334/PRO533]
Publications[править]
Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease. Approximately 30% of patients do not respond to therapy with ursodeoxycholic acid (UDCA). Previous studies have implicated increased senescence of cholangiocytes in patients who do not respond to UDCA. This may increase the release of cytokines which drive pathogenic T cell polarization. As FXR agonists are beneficial in treating UDCA non-responsive patients, the current study was designed to model the interactions between cholangiocytes and CD4 T cells to investigate potential immunomodulatory mechanisms of bile acid receptor agonists. Human cholangiocytes were co-cultured with CD4 T cells to model the biliary stress response. Senescent cholangiocytes were able to polarize T cells toward a Th17 phenotype and suppressed expression of FoxP3 ([i]P[/i] = 0.0043). Whilst FXR and TGR5 receptor agonists were unable directly to alter cholangiocyte cytokine expression, FGF19 was capable of significantly reducing IL-6 release ([i]P[/i] = 0.044). Bile acid receptor expression was assessed in PBC patients with well-characterized responsiveness to UDCA therapy. A reduction in FXR staining was observed in both cholangiocytes and hepatocytes in PBC patients without adequate response to UDCA. Increased IL-6 expression by senescent cholangiocytes represents a potential mechanism by which biliary damage in PBC could contribute to excessive inflammation.
Keywords
- FGF19
- FXR
- TGR5
- autoimmunity
- senescence
Three fibroblast growth factor(FGF) members, FGF19, FGF21, and FGF23, function as endocrine factors that regulate various metabolic processes. The unique feature of these endo- crine FGFs is the fact that they require Klotho proteins to bind to their cognate FGF recep- tors. Defects in Klotho or FGF23 result in disturbed mineral metabolism and accelerated aging. The aging phenotypes can be alleviated by correcting phosphate imbalance, leading us to hypothesize that phosphate accelerates aging. In contrast, overexpression of FGF21 extends life span in mice. Thus, the FGF-Klotho endocrine axes have emerged as key regula- tors of the aging process and are regarded as potential therapeutic targets for the treatment of age-related disorders.
MeSH Terms
- Aging
- Animals
- Fibroblast Growth Factors
- Glucuronidase
- Humans
- Longevity
- Mice
The Klotho proteins, αKlotho and βKlotho, are essential components of endocrine fibroblast growth factor (FGF) receptor complexes, as they are required for the high-affinity binding of FGF19, FGF21 and FGF23 to their cognate FGF receptors (FGFRs). Collectively, these proteins form a unique endocrine system that governs multiple metabolic processes in mammals. FGF19 is a satiety hormone that is secreted from the intestine on ingestion of food and binds the βKlotho-FGFR4 complex in hepatocytes to promote metabolic responses to feeding. By contrast, under fasting conditions, the liver secretes the starvation hormone FGF21, which induces metabolic responses to fasting and stress responses through the activation of the hypothalamus-pituitary-adrenal axis and the sympathetic nervous system following binding to the βKlotho-FGFR1c complex in adipocytes and the suprachiasmatic nucleus, respectively. Finally, FGF23 is secreted by osteocytes in response to phosphate intake and binds to αKlotho-FGFR complexes, which are expressed most abundantly in renal tubules, to regulate mineral metabolism. Growing evidence suggests that the FGF-Klotho endocrine system also has a crucial role in the pathophysiology of ageing-related disorders, including diabetes, cancer, arteriosclerosis and chronic kidney disease. Therefore, targeting the FGF-Klotho endocrine axes might have therapeutic benefit in multiple systems; investigation of the crystal structures of FGF-Klotho-FGFR complexes is paving the way for the development of drugs that can regulate these axes.
MeSH Terms
- Aging
- Animals
- Biomarkers
- Birds
- Cardiovascular Diseases
- Endocrine System Diseases
- Fibroblast Growth Factors
- Glucuronidase
- Humans
- Hypothalamo-Hypophyseal System
- Kidney Diseases
- Mammals
- Phosphates
- Pituitary-Adrenal System
To clarify appropriateness of current claims for health and wellness virtues of argan oil, studies were conducted in inflammatory states. LPS induces inflammation with reduction of PGC1-[i]α[/i] signaling and energy metabolism. Argan oil protected the liver against LPS toxicity and interestingly enough preservation of peroxisomal acyl-CoA oxidase type 1 (ACOX1) activity against depression by LPS. This model of LPS-driven toxicity circumvented by argan oil along with a key anti-inflammatory role attributed to ACOX1 has been here transposed to model aging. This view is consistent with known physiological role of ACOX1 in yielding precursors of specialized proresolving mediators (SPM) and with characteristics of aging and related disorders including reduced PGC1-[i]α[/i] function and improvement by strategies rising ACOX1 (via hormonal gut FGF19 and nordihydroguaiaretic acid in metabolic syndrome and diabetes conditions) and SPM (neurodegenerative disorders, atherosclerosis, and stroke). Delay of aging to resolve inflammation results from altered production of SPM, SPM improving most aging disorders. The strategic metabolic place of ACOX1, upstream of SPM biosynthesis, along with ability of ACOX1 preservation/induction and SPM to improve aging-related disorders and known association of aging with drop in ACOX1 and SPM, all converge to conclude that ACOX1 represents a previously unsuspected and currently emerging antiaging protein.
MeSH Terms
- Acyl-CoA Oxidase
- Aging
- Animals
- Anti-Inflammatory Agents
- Disease Models, Animal
- Humans
- Lipopolysaccharides
- Oxidoreductases
- Plant Oils
The counterregulatory response to hypoglycemia, which restores normal blood glucose levels to ensure sufficient provision of glucose to the brain, is critical for survival. To discover underlying brain regulatory systems, we performed a genetic screen in recombinant inbred mice for quantitative trait loci (QTL) controlling glucagon secretion in response to neuroglucopenia. We identified a QTL on the distal part of chromosome 7 and combined this genetic information with transcriptomic analysis of hypothalami. This revealed Fgf15 as the strongest candidate to control the glucagon response. Fgf15 was expressed by neurons of the dorsomedial hypothalamus and the perifornical area. Intracerebroventricular injection of FGF19, the human ortholog of Fgf15, reduced activation by neuroglucopenia of dorsal vagal complex neurons, of the parasympathetic nerve, and lowered glucagon secretion. In contrast, silencing Fgf15 in the dorsomedial hypothalamus increased neuroglucopenia-induced glucagon secretion. These data identify hypothalamic Fgf15 as a regulator of glucagon secretion.
MeSH Terms
- Aging
- Animals
- Chromosomes, Mammalian
- Deoxyglucose
- Fibroblast Growth Factors
- Gene Silencing
- Genetic Testing
- Genome
- Glucagon
- Hypothalamus
- Mice, Inbred C57BL
- Parasympathetic Nervous System
- Quantitative Trait Loci
Keywords
- FGF15
- FGF19
- QTL mapping
- autonomic nervous system
- dorsal vagal complex
- genetic screen
- glucagon secretion
- glucose sensing
- hypothalamus
- neuroglucopenia
Although the number of centenarians is growing worldwide, the potential factors influencing the aging process remain only partially elucidated. Researchers are increasingly focusing toward biomarkers as tools to shed more light on the pathophysiology of complex phenotypes, including the ability to reach successful aging, i.e., free of major chronic diseases. We therefore conducted a case-control study examining the potential associations of multiple candidate biomarkers in healthy centenarians and sex-matched healthy elderly controls. Using a case-control study of 81 centenarians (aged ≥ 100 years) selected based on the fact that they were disease-free and 46 healthy elderly controls (aged 70-80 years), serum levels of 15 different candidate biomarkers involved in the regulation of metabolism, angiogenesis, inflammation, and bone formation were measured. Of the 15 biomarkers tested, four molecules (chemerin, fetuin-A, and fibroblast growth factors [FGF] 19 and 21) were found to be independently associated with successful aging regardless of sex. Logistic regression analysis confirmed that chemerin, fetuin-A, FGF19, and FGF21 were independently associated with successful aging [predicted probability (PP) = 1 / [1 1 / exp (11.832 - 0.027 × (chemerin) - 0.009 × (fetuin-A) 0.014 × (FGF19) - 0.007 × (FGF21)]. The area under the curve (AUC) of predicted probability values for the four-biomarker panel revealed that it can discriminate between centenarians and elderly controls with excellent accuracy (AUC > 0.94, P < 0.001). Although preliminary in essence and limited by the low sample size and lack of replication in other independent cohorts, our data suggest an independent association between successful aging and serum chemerin, fetuin-A, FGF19, and FGF21, which may provide novel information on the mechanisms behind the human aging process. Whether the four-biomarker panel may predict successful aging deserves further scrutiny.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Biomarkers
- Case-Control Studies
- Chemokines
- Female
- Fetuins
- Fibroblast Growth Factors
- Humans
- Intercellular Signaling Peptides and Proteins
- Male
- Predictive Value of Tests
Endocrine fibroblast growth factors (FGFs) have been recognized as hormones that regulate a variety of metabolic processes. FGF19 is secreted from intestine upon feeding and acts on liver to suppress bile acid synthesis. FGF21 is secreted from liver upon fasting and acts on adipose tissue to promote lipolysis and responses to fasting. FGF23 is secreted from bone and acts on kidney to inhibit phosphate reabsorption and vitamin D synthesis. One critical feature of endocrine FGFs is that they require the Klotho gene family of transmembrane proteins as coreceptors to bind their cognate FGF receptors and exert their biological activities. This chapter overviews function of Klotho family proteins as obligate coreceptors for endocrine FGFs and discusses potential link between Klothos and age-related diseases.
MeSH Terms
- Aging
- Animals
- Glucuronidase
- Homeostasis
- Humans
- Membrane Proteins
- Phosphates
- Receptors, Cytoplasmic and Nuclear
FGF19, FGF21, and FGF23 form a unique subfamily of fibroblast growth factors. Because they contain intra-molecular disulfide bonds and show reduced affinity toward heparan sulfate located in the extracellular space, it is thought that, in contrast to other FGFs, they function as endocrine hormones. FGF23 and its co-receptor alphaKlotho are involved in the control of aging, but it is not known if the same holds true for FGF19, which can also signal through alphaKlotho. However, considerable evidence supports a role for FGF19 in controlling various aspects of metabolism. We have recently fully characterized FGF19/FGFR/co-factor interactions and signaling, and in the current manuscript discuss the contribution of the FGF19/FGFR4 axis to bile acid and glucose regulation.
MeSH Terms
- Animals
- Bile Acids and Salts
- Blood Glucose
- Fibroblast Growth Factors
- Homeostasis
- Humans
- Mice
- Receptor, Fibroblast Growth Factor, Type 4
Keywords
- FGF19
- FGF21
- FGF23
- aging
- diabetes
- fibroblast growth factors
- insulin
- metabolic diseases