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β-Klotho (KLB) is a member of the Klotho protein family, which is mainly distributed in organs and tissues such as the liver, fat, pancreas, and brain. KLB is a single-pass transmembrane protein whose structural characteristics determine that KLB acts as a co-receptor for fibroblast growth factor (FGF) 19/21 targeting the activation of fibroblast growth factor receptor (FGFRs). KLB is involved in the regulation of blood glucose, lipids, body weight, bile acid circulation, and hepatocyte proliferation in the FGF21/19-KLB-FGFRs pathway. This paperwill review the structural characteristics and distribution of KLB, as well as the regulatory mechanism of material energy and its role in tumor formation in the FGF19/21-KLB-FGFRs pathways.
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Sarcopenia obesity (SO), a specific disease with co-occurrence of obesity and sarcopenia, is shown clinically as abnormal accumulation of fat, decreased mass and strength of muscle, and increased risk of incidence and mortality of other chronic diseases. Currently, there exist various definitions and diagnoses about SO in the various regions of the world. Its prevalence in populations elevates in an age-dependent manner. This article summarized the possible pathogenesis of SO from the view of chronic inflammation, oxidative stress, insulin resistance, and Hippo pathway, subsequently listed and analyzed potential pharmacological targets (fibroblast growth factor, CD44, adiponectin, etc) involved in treating SO, in order to provide new ideas for clinical diagnosis, treatment of SO patients and research and development of innovative drugs.
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OBJECTIVES: Previous studies have not shown any correlation between bile acid metabolism and bone mineral density (BMD) in women with postmenopausal osteoporosis. Thus, the current study evaluated the association between bile acid levels as well as BMD and bone turnover marker levels in this group of women. METHODS: This single-center cross-sectional study included 150 postmenopausal Chinese women. According to BMD, the participants were divided into three groups: osteoporosis group, osteopenia group, and healthy control group. Serum bile acid, fibroblast growth factor 19 (FGF19), and bone turnover biomarker levels were assessed. Moreover, the concentrations of parathyroid hormone, 25-hydroxy vitamin D [25(OH)D], procollagen type I N-peptide (P1NP), and beta-CrossLaps of type I collagen containing cross-linked C-terminal telopeptide (β-CTX) were evaluated. The BMD of the lumbar spine and proximal femur were examined via dual-energy X-ray absorptiometry. RESULTS: The serum total bile acid levels in the osteoporosis and osteopenia groups (5.28±1.56 and 5.31±1.56 umol/L, respectively) were significantly lower than that in the healthy control group (6.33±2.04 umol/L; p=0.002 and 0.018, respectively). Serum bile acid level was positively associated with the BMD of the lumbar spine, femoral neck, and total hip. However, it negatively correlated with β-CTX concentration. Moreover, no correlation was observed between bile acid and P1NP levels, and the levels of the other biomarkers that were measured did not differ between the groups. CONCLUSION: Serum bile acid was positively correlated with BMD and negatively correlated with bone turnover biomarkers reflecting bone absorption in postmenopausal women. Thus, bile acid may play an important role in bone metabolism.
Subject(s)
Humans , Female , Middle Aged , Bone Density , Bile , Biomarkers , Absorptiometry, Photon , Osteoporosis, Postmenopausal , Cross-Sectional Studies , Bone Remodeling , Postmenopause , Collagen Type IABSTRACT
Objective: To assess the potential value of fibroblast growth factor 19 (FGF19) as predictors of gastrointestinal dysfunction in children with sepsis. Methods: A prospective study was conducted, and 101 pediatric patients diagnosed with sepsis and admitted to the pediatric intensive care unit (PICU) at Shanghai Children's Hospital, Shanghai Jiao Tong University were enrolled from January 2018 to December 2018. Eleven cases with missing serum FGF19 were excluded, and 90 cases were analyzed in this study. According to whether gastrointestinal dysfunction occurred in patients with sepsis during PICU hospitalization, patients were divided into two groups, including sepsis-associated ga-strointestinal dysfunction group (n=32) and sepsis without gastrointestinal dysfunction group (n=58). Serum FGF19 level was determined on PICU admission. The difference of serum FGF19 levels between the two groups were compared by using Mann-Whitney U test, and multivariate Logistic regression analysis was used to assess the association of FGF19 level with sepsis-associated ga-strointestinal dysfunction. Results: The total PICU mortality rate was 12.2% (11/90). There was a tendency for increased PICU mortality in patients with sepsis-associated gastrointestinal dysfunction compared with patients without gastrointestinal dysfunction, but without statistical significance (18.8% vs 8.6%, P=0.160). Serum FGF19 levels were significantly decreased in patients with sepsis-associated gastrointestinal dysfunction compared with patients without gastrointestinal dysfunction [48.4 (27.7, 95.6) μg/mL vs 77.6 (45.8, 151.2) μg/mL, P=0.046]. The results of receiver operating characteristic (ROC) curve analysis showed that the area under ROC curve (AUC) for FGF19 predicting gastrointestinal dysfunction in pediatric patients with sepsis was 0.636 (95%CI 0.515-0.757), which was similar to the predictive capacity of procalcitonin [AUC=0.683 (95%CI 0.562-0.804), P=0.597]. In addition, serum FGF19 levels lower than 60 μg/mL on PICU admission indicated an increased risk of gastrointestinal dysfunction in pediatric patients with sepsis. Conclusion: Serum FGF19 is a novel predictor of gastrointestinal dysfunction in pediatric patients with sepsis.
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Members of the fibroblast growth factor (FGF) family play pleiotropic roles in cellular and metabolic homeostasis. During evolution, the ancestor FGF expands into multiple members by acquiring divergent structural elements that enable functional divergence and specification. Heparan sulfate-binding FGFs, which play critical roles in embryonic development and adult tissue remodeling homeostasis, adapt to an autocrine/paracrine mode of action to promote cell proliferation and population growth. By contrast, FGF19, 21, and 23 coevolve through losing binding affinity for extracellular matrix heparan sulfate while acquiring affinity for transmembrane α-Klotho (KL) or β-KL as a coreceptor, thereby adapting to an endocrine mode of action to drive interorgan crosstalk that regulates a broad spectrum of metabolic homeostasis. FGF19 metabolic axis from the ileum to liver negatively controls diurnal bile acid biosynthesis. FGF21 metabolic axes play multifaceted roles in controlling the homeostasis of lipid, glucose, and energy metabolism. FGF23 axes from the bone to kidney and parathyroid regulate metabolic homeostasis of phosphate, calcium, vitamin D, and parathyroid hormone that are important for bone health and systemic mineral balance. The significant divergence in structural elements and multiple functional specifications of FGF19, 21, and 23 in cellular and organismal metabolism instead of cell proliferation and growth sufficiently necessitate a new unified and specific term for these three endocrine FGFs. Thus, the term "FGF Metabolic Axis," which distinguishes the unique pathways and functions of endocrine FGFs from other autocrine/paracrine mitogenic FGFs, is coined.
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[Summary] Bile acid is a main component of bile ,which plays a key role in keeping cholesterol metabolism balance in vivo and promoting lipids digestion in intestine. Recently ,more and more researches focus on bile acid for its regulating effect on glucose ,lipid and energy metabolism as a signal molecule. The reabsorbed bile acid stimulates the secretion of fibroblast growth factor 19 (FGF19) and glucagon-like peptide-1(GLP-1) in the intestine by activating a nuclear receptor farnesoid X-activated receptor (FXR) and a membrane receptor TGR5. FGF19 and GLP-1 regulate hepatic glucose metabolism through different pathways. Here ,we briefly summarize the research progress and relationship between bile acid induced gut hormones and hepatic glucose metabolism.
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Bile acid diarrhea (BAD) is usually seen in patients with ileal Crohn's disease or ileal resection. However, 25% to 50% of patients with functional diarrhea or diarrhea-predominant irritable bowel syndrome (IBS-D) also have evidence of BAD. It is estimated that 1% of the population may have BAD. The causes of BAD include a deficiency in fibroblast growth factor 19 (FGF-19), a hormone produced in enterocytes that regulates hepatic bile acid (BA) synthesis. Other potential causes include genetic variations that affect the proteins involved in BA enterohepatic circulation and synthesis or in the TGR5 receptor that mediates the actions of BA in colonic secretion and motility. BAs enhance mucosal permeability, induce water and electrolyte secretion, and accelerate colonic transit partly by stimulating propulsive high-amplitude colonic contractions. There is an increased proportion of primary BAs in the stool of patients with IBS-D, and some changes in the fecal microbiome have been described. There are several methods of diagnosing BAD, such as 75selenium homotaurocholic acid test retention, serum C4, FGF-19, and fecal BA measurement; presently, therapeutic trials with BA sequestrants are most commonly used for diagnosis. Management involves the use of BA sequestrants including cholestyramine, colestipol, and colesevelam. FXR agonists such as obeticholic acid constitute a promising new approach to treating BAD.
Subject(s)
Humans , Anticholesteremic Agents/therapeutic use , Bile Acids and Salts/physiology , Crohn Disease/complications , Diarrhea/etiology , Feces/chemistry , Fibroblast Growth Factors/deficiency , Gastrointestinal Microbiome , Irritable Bowel Syndrome/complicationsABSTRACT
Objectives To analyze the expression of fibroblast growth factor-19(FGF-19) in hepatocellular carcinoma ( HCC) and adjacent tissues , and to investigate its clinical significance .Methods A total of 209 HCC patients who had undergone radical resection operations at Hospital 401 between January 2003 and December 2009 were chosen as samples . Immunohistochemistry method was employed to examine the expression level of FGF-19 in HCC and adjacent tissues .The relationship between FGF-19 protein expressions and clinicopathological features was analyzed by the chi -square test or Fisher exact probability .A survival curve was drawn using the Kaplan-Meier method and the Cox model was used to analyze factors that influenced survival .Results The rate of high expression of FGF-19 was 66.1% (138/209) in HCC, which was significantly higher than 46.9%(98/209) in adjacent tissues (P<0.05).The high expression of FGF-19 was related to the tumor capsule and tumor boundary (P<0.05).The overall survival in high expression of FGF-19 group was signifi-cantly lower than that in low expression group (P<0.05).Conclusion FGF-19 plays an important role in the carcinogen-esis and development of HCC , and a high expression of FGF-19 might be closely related to survival time of postoperative patients.FGF-19 might be a potential prognosis prediction factor for HCC .