Fibroblast Growth Factor 21 Mimetics for Treating Atherosclerosis.
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ABSTRACT:
SUBMITTER: Kwok KHM
PROVIDER: S-EPMC5503858 | biostudies-other | 2017 Jun
REPOSITORIES: biostudies-other
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Project description:BackgroundFGF21 is a critical endogenous regulator in energy homeostasis and systemic glucose and lipid metabolism. Despite intensive study of the metabolic functions of FGF21, its important role in heart disease needs further exploration. Apoptosis induced by ox-LDL in vascular endothelial cells is an important step in the progress of atherosclerosis.MethodsThe effects of FGF21 treatment on apoptosis induced by ox-LDL were tested in HUVECs. The role of FGF21 in atherosclerosis was studied by evaluating its function in apolipoprotein E double knockout (apoE-/-) mice.ResultsWe found that apoptosis in HUVECs was alleviated by FGF21 treatment. The effects of FGF21 were independent of the ERK1/2 pathway and were mediated through inhibition of the Fas signaling pathway. FGF21 suppressed the development of atherosclerosis, and the administration of FGF21 ameliorated Fas-mediated apoptosis in apoE-/- mice.ConclusionFGF21 protects against apoptosis in HUVECs by suppressing the expression of Fas; furthermore, FGF21 alleviated atherosclerosis by ameliorating Fas-mediated apoptosis in apoE-/- mice.
| S-EPMC6114502 | biostudies-literature
Project description:FGF21 is a stress-induced hormone with potent anti-obesity, insulin-sensitizing, and hepatoprotective properties. Although proteolytic cleavage of recombinant human FGF21 in preclinical species has been observed previously, the regulation of endogenously produced FGF21 is not well understood. Here we identify fibroblast activation protein (FAP) as the enzyme that cleaves and inactivates human FGF21. A selective chemical inhibitor, immunodepletion, or genetic deletion of Fap stabilized recombinant human FGF21 in serum. In addition, administration of a selective FAP inhibitor acutely increased circulating intact FGF21 levels in cynomolgus monkeys. On the basis of our findings, we propose selective FAP inhibition as a potential therapeutic approach to increase endogenous FGF21 activity for the treatment of obesity, type 2 diabetes, non-alcoholic steatohepatitis, and related metabolic disorders.
| S-EPMC4786731 | biostudies-literature
Project description:BackgroundFibroblast growth factor 21 (FGF21) may play a role in the development of chronic kidney disease (CKD). We therefore investigated the relationship of plasma FGF21 levels with kidney function and albuminuria in the Multi-Ethnic Study of Atherosclerosis (MESA).MethodsThe analysis included 5724 MESA participants ages 45-84 years between 2000 and 2002, free of clinically apparent cardiovascular disease (CVD). Participants were followed up in person at four additional clinic visits over 10 years. Plasma FGF21 levels were measured at baseline examination by enzyme-linked immunosorbent assay. Kidney function was assessed by estimated glomerular filtration rate (eGFR). Outcomes were urinary albumin:creatinine ratio (UACR) progression, incident CKD by eGFR (reaching eGFR <60 mL/min/1.73 m2 with eGFR loss rate ≥1 mL/min/1.73 m2 per year) and rapid kidney function decline (eGFR decline >5%/year).ResultsAt baseline, higher FGF21 levels, assessed as both continuous and categorical quartile variables, were significantly associated with lower eGFR and higher UACR, after adjusting for demographic, socioeconomic and other confounding factors [adjusted mean differences of -2.63 mL/min/1.73 m2 in eGFR and 0.134 in log normally transformed UACR (mg/g) for the highest FGF21 quartile compared with the lowest quartile, all P < 0.001]. However, in longitudinal analyses, baseline FGF21 levels did not predict incident CKD by eGFR, rapid kidney function decline or UACR progression. No significant interaction with sex and race/ethnicity was found (all P > 0.05).ConclusionsOur study does not support a role of FGF21 as a biomarker for predicting kidney function decline or albuminuria in adults free of clinically apparent CVD at baseline.
| S-EPMC6545465 | biostudies-literature
Project description:Fibroblast growth factor 21 (FGF21) is a member of the endocrine FGF family that acts as a metabolic regulator of both glucose and lipid metabolism. Similar to fibroblast growth factor 23 (FGF23), serum FGF21 levels rise progressively with the loss of renal function, reaching 20 times normal values in end-stage renal disease. In patients with chronic kidney disease (CKD), higher serum FGF21 levels correlate with poorer metabolic profile, higher inflammatory markers, more comorbidities, and higher mortality. The high serum FGF21 levels are above and beyond what can be explained by the loss of FGF21 renal clearance, suggesting increased production and/or impaired non-renal clearance. In diabetic nephropathy, serum FGF21 levels correlate with the severity of albuminuria and faster loss of glomerular filtrate rate and can potentially be a biomarker of poor prognostic. The observational and associative human data contrast sharply with in vitro and in vivo preclinical experimental data, which is more in line with a protective role of FGF21 in chronic nephropathies. We here review the physiology of FGF21, and the literature regarding its behavior in CKD with particular focus on diabetic nephropathy. Finally, we speculate on the role of FGF21 in CKD.
| S-EPMC6483847 | biostudies-literature
Project description:Glucagon, an essential regulator of glucose homeostasis, also modulates lipid metabolism and promotes weight loss, as reflected by the wasting observed in glucagonoma patients. Recently, coagonist peptides that include glucagon agonism have emerged as promising therapeutic candidates for the treatment of obesity and diabetes. We developed a novel stable and soluble glucagon receptor (GcgR) agonist, which allowed for in vivo dissection of glucagon action. As expected, chronic GcgR agonism in mice resulted in hyperglycemia and lower body fat and plasma cholesterol. Notably, GcgR activation also raised hepatic expression and circulating levels of fibroblast growth factor 21 (FGF21). This effect was retained in isolated primary hepatocytes from wild-type (WT) mice, but not GcgR knockout mice. We confirmed this link in healthy human volunteers, where injection of natural glucagon increased plasma FGF21 within hours. Functional relevance was evidenced in mice with genetic deletion of FGF21, where GcgR activation failed to induce the body weight loss and lipid metabolism changes observed in WT mice. Taken together, these data reveal for the first time that glucagon controls glucose, energy, and lipid metabolism at least in part via FGF21-dependent pathways.
| S-EPMC3636653 | biostudies-literature
Project description:BackgroundSkeletal muscle is a plastic tissue that adapts to changes in exercise, nutrition, and stress by secreting myokines and myometabolites. These muscle-secreted factors have autocrine, paracrine, and endocrine effects, contributing to whole body homeostasis. Muscle dysfunction in aging sarcopenia, cancer cachexia, and diabetes is tightly correlated with the disruption of the physiological homeostasis at the whole body level. The expression levels of the myokine fibroblast growth factor 21 (FGF21) are very low in normal healthy muscles. However, fasting, ER stress, mitochondrial myopathies, and metabolic disorders induce its release from muscles. Although our understanding of the systemic effects of muscle-derived FGF21 is exponentially increasing, the direct contribution of FGF21 to muscle function has not been investigated yet.MethodsMuscle-specific FGF21 knockout mice were generated to investigate the consequences of FGF21 deletion concerning skeletal muscle mass and force. To identify the mechanisms underlying FGF21-dependent adaptations in skeletal muscle during starvation, the study was performed on muscles collected from both fed and fasted adult mice. In vivo overexpression of FGF21 was performed in skeletal muscle to assess whether FGF21 is sufficient per se to induce muscle atrophy.ResultsWe show that FGF21 does not contribute to muscle homeostasis in basal conditions in terms of fibre type distribution, fibre size, and muscle force. In contrast, FGF21 is required for fasting-induced muscle atrophy and weakness. The mass of isolated muscles from control-fasted mice was reduced by 15-25% (P < 0.05) compared with fed control mice. FGF21-null muscles, however, were significantly protected from muscle loss and weakness during fasting. Such important protection is due to the maintenance of protein synthesis rate in knockout muscles during fasting compared with a 70% reduction in control-fasted muscles (P < 0.01), together with a significant reduction of the mitophagy flux via the regulation of the mitochondrial protein Bnip3. The contribution of FGF21 to the atrophy programme was supported by in vivo FGF21 overexpression in muscles, which was sufficient to induce autophagy and muscle loss by 15% (P < 0.05). Bnip3 inhibition protected against FGF21-dependent muscle wasting in adult animals (P < 0.05).ConclusionsFGF21 is a novel player in the regulation of muscle mass that requires the mitophagy protein Bnip3.
| S-EPMC6596457 | biostudies-literature
Project description:Fibroblast growth factor 21 (FGF21) is a recently discovered hepatokine that regulates lipid and glucose metabolism and is upregulated in response to numerous physiological and pathological stimuli. Herein, we demonstrate that both physical and chemical hypoxia increase the systemic and hepatic expression of FGF21 in mice; by contrast, hypoxia induces a reduction of FGF21 expression in hepatocytes, indicating that hypoxia-induced FGF21 expression is differentially regulated in intact animals and in hepatocytes. Furthermore, we demonstrate that hypoxia treatment increases hormone-sensitive lipase-mediated adipose tissue lipolysis in mice, which is reduced in Fgf21 knockout mice, thereby implying that FGF21 plays a critical role in hypoxia-related adipose lipolysis. Adipose tissue lipolysis causes an increase in the amount of circulating free fatty acids, which leads to the activation of peroxisome proliferators-activated receptor alpha and an increased expression of FGF21 in hepatocytes. We further show that hypoxia-induced elevation of reactive oxygen species, but not the hypoxia-inducible factor, is responsible for the lipolysis and FGF21 expression. In conclusion, our data clearly demonstrate that FGF21 plays a critical role in hypoxia-induced adipose lipolysis, which induces hepatic expression of FGF21. Clarification of hypoxia-regulated FGF21 regulation will enhance our understanding of the pathophysiology of hypoxia-related diseases, such as sleep disorders and metabolic diseases.
| S-EPMC7456904 | biostudies-literature
Project description:ObjectiveFructose consumption is a risk factor for metabolic disease. We recently demonstrated that fibroblast growth factor 21 (FGF21), a metabolic hormone involved in lipid and glucose metabolism, is acutely stimulated in humans by 75 g oral fructose, with peak levels occurring 2 h after consumption. This study reports on the dose dependency and reproducibility of the FGF21 response to fructose.MethodsLean, healthy adults drank either five different doses of fructose dissolved in water, each separated by 2 weeks, or the same dose on three occasions, each separated by 1 week.ResultsFibroblast growth factor 21 levels peaked at 2 h in a dose-dependent manner. No significant increase in FGF21 was seen after consumption of 10 g fructose, while robust increases were seen after drinking solutions containing 30, 50 and 75 g. At 2 h, the minimal fold change of FGF21 was highest following a 75 g fructose drink, and all subjects demonstrated at least a doubling of FGF21 levels following consumption of this dose.ConclusionsThe increase in FGF21 following an oral fructose challenge is dose dependent, with levels peaking at 2 h independent of dose. The FGF21 response to 75 g fructose is also highly reproducible within individuals.Clinical implicationsBy demonstrating that the FGF21 response to fructose is dose dependent and reproducible, this study deepens current understanding of FGF21 fructose dynamics and physiology in humans. This is an important area of clinical interest given associations between fructose intake and a wide variety of metabolic derangements.
| S-EPMC6180711 | biostudies-literature
Project description:BackgroundFibroblast growth factor 21 (FGF21) increases glucose uptake. It is unknown if FGF21 serum levels are affected by exercise.Methodology/principal findingsThis was a comparative longitudinal study. Anthropometric and biochemical evaluation were carried out before and after a bout of exercise and repeated after two weeks of daily supervised exercise. The study sample was composed of 60 sedentary young healthy women. The mean age was 24±3.7 years old, and the mean BMI was 21.4±7.0 kg/m². The anthropometric characteristics did not change after two weeks of exercise. FGF21 levels significantly increased after two weeks of exercise (276.8 ng/l (142.8-568.6) vs. (460.8 (298.2-742.1), p<0.0001)). The delta (final-basal) log of serum FGF21, adjusted for BMI, showed a significant positive correlation with basal glucose (r = 0.23, p = 0.04), mean maximal heart rate (MHR) (r = 0.54, p<0.0001), mean METs (r = 0.40, p = 0.002), delta plasma epinephrine (r = 0.53, p<0.0001) and delta plasma FFAs (r = 0.35, p = 0.006). A stepwise linear regression model showed that glucose, MHR, METs, FFAs, and epinephrine, were factors independently associated with the increment in FGF21 after the exercise program (F = 4.32; r² = 0.64, p<0.0001).ConclusionsSerum FGF21 levels significantly increased after two weeks of physical activity. This increment correlated positively with clinical parameters related to the adrenergic and lipolytic response to exercise.Trial registrationClinicalTrials.gov NCT01512368.
| S-EPMC3365112 | biostudies-literature
Project description:Background FGF21 (fibroblast growth factor 21), a novel hepatokine regulating lipid metabolism, has been linked to atherosclerotic disease. However, whether this relationship exists in patients without nonalcoholic fatty liver disease is unclear. We assessed the association between serum FGF21 levels and atherosclerosis in patients without nonalcoholic fatty liver disease, and investigated whether baseline FGF21 could predict incident atherosclerotic cardiovascular disease in a 7-year prospective cohort. Methods and Results Baseline serum FGF21 was measured in a cross-sectional cohort of 371 patients with type 2 diabetes mellitus without nonalcoholic fatty liver disease (determined by hepatic magnetic resonance spectroscopy), and in a population-based prospective cohort of 705 patients from the Shanghai Diabetes Study. In the cross-sectional study, FGF21 was significantly higher in patients with than in those without subclinical carotid atherosclerosis (P<0.01). The association remained significant after adjusting for demographic and traditional cardiovascular risk factors. In the prospective cohort, 80 patients developed atherosclerotic cardiovascular disease during follow-up. Baseline FGF21 was significantly higher in those who developed ischemic heart disease or cerebral infarction than in those who did not. Using a cutoff serum concentration of 232.0 pg/mL, elevated baseline FGF21 independently predicted incident total atherosclerotic cardiovascular disease events, ischemic heart disease, and cerebral infarction in a nondiabetic population (all P<0.05), and significantly improved the discriminatory and reclassifying abilities of our prediction model after adjustment for established cardiovascular risk factors. Conclusions This study provides the first evidence that FGF21 levels are elevated in patients without nonalcoholic fatty liver disease with subclinical atherosclerosis. Baseline FGF21 is an independent predictor of atherosclerotic cardiovascular disease and represents a novel biomarker for primary prevention in the general population.
| S-EPMC7428997 | biostudies-literature