Fgf21 Gene Research Articles

Genetic aspects of taste formation

The article discusses the molecular genetic basis of taste development which determines the peculiarity of perception of sweet, salty, sour, bitter and high-protein food (umami). The genes TAS1R3, FTO, GLUT2, FGF21, GNAT3 are responsible for individual perception of sugar volume. Serum FGF21 levels are significantly elevated in obese patients and in patients with type 2 diabetes mellitus which presumably indicates a state of resistance to FGF21. Given the role of refined sugars in the development of diseases, the use of foods with a reduced content or complete absence of added sugar is a worldwide trend, especially necessary in the nutrition of children. During genome-wide sequencing for 39 patients aged 15-18 years, FGF21 gene polymorphism was detected in 27 adolescents (69 %) without gender identity. Almost all patients with FGF21 gene polymorphism showed a high addiction to sweet foods. Currently, the existence of a sixth taste is being debated, it is ammonium chloride, whose receptors are regulated by the Otop1 gene which is also responsible for the identification of sour taste.

Fibroblast growth factor 21 is a hepatokine involved in MASLD progression.

We aimed to assess the role of FGF21 in metabolic dysfunction-associated steatotic liver disease (MASLD) at a multi-scale level. We used human MASLD pathology samples for FGF21 gene expression analyses (qPCR and RNAseq), serum to measure circulating FGF21 levels and DNA for genotyping the FGF21 rs838133 variant in both estimation and validation cohorts. A hepatocyte-derived cell line was exposed to free fatty acids at different timepoints. Finally, C57BL/6J mice were fed a high-fat and choline-deficient diet (CDA-HFD) for 16weeks to assess hepatic FGF21 protein expression and FGF21 levels by ELISA. A significant upregulation in FGF21 mRNA expression was observed in the liver analysed by both qPCR (fold change 5.32±5.25 vs. 0.59±0.66; p=0.017) and RNA-Seq (3.5 fold; FDR: 0.006; p<0.0001) in MASLD patients vs. controls. Circulating levels of FGF21 were increased in patients with steatohepatitis vs. bland steatosis (386.6±328.9 vs. 297.9±231.5 pg/mL; p=0.009). Besides, sex, age, A-allele from FGF21, GG genotype from PNPLA3, ALT, type 2 diabetes mellitus and BMI were independently associated with MASH and significant fibrosis in both estimation and validation cohorts. In vitro exposure of Huh7.5 cells to high concentrations of free fatty acids (FFAs) resulted in overexpression of FGF21 (p<0.001). Finally, Circulating FGF21 levels and hepatic FGF21 expression were found to be significantly increased (p<0.001) in animals under CDA-HFD. Hepatic and circulating FGF21 expression was increased in MASH patients, in Huh7.5 cells under FFAs and in CDA-HFD animals. The A-allele from the rs838133 variant was also associated with an increased risk of steatohepatitis and significant and advanced fibrosis in MASLD patients.

Mesenchymal stem/stromal cells armored by FGF21 ameliorate alcohol-induced liver injury through modulating polarization of macrophages.

Alcohol-associated liver disease (ALD) is a major health care challenge worldwide with limited therapeutic options. Although mesenchymal stem/stromal cells (MSCs) represent a newly emerging therapeutic approach to treat ALD, thus far, there have been extensive efforts to try and enhance their efficacy, including genetically engineering MSCs. FGF21, an endocrine stress-responsive hormone, has been shown to regulate energy balance, glucose, and lipid metabolism and to enhance the homing of MSCs toward injured sites. Therefore, the purpose of this study was to investigate whether MSCs that overexpress FGF21 (FGF21-MSCs) improve the therapeutic effect of MSCs in treating ALD. Human umbilical cord-derived MSCs served as the gene delivery vehicle for the FGF21 gene. Human umbilical cord-derived MSCs were transduced with the FGF21 gene using lentiviral vectors to mediate FGF21 overexpression. We utilized both chronic Lieber-DeCarli and Gao-binge models of ethanol-induced liver injury to observe the therapeutic effect of FGF21-MSCs. Liver injury was phenotypically evaluated by performing biochemical methods, histology, and inflammatory cytokine levels. Compared with MSCs alone, administration of MSCs overexpressing FGF21(FGF21-MSCs) treatment significantly enhanced the therapeutic effect of ALD in mice, as indicated by the alleviation of liver injury with reduced steatosis, inflammatory infiltration, oxidative stress, and hepatic apoptosis, and the promotion of liver regeneration. Mechanistically, FGF21 could facilitate the immunomodulatory function of MSCs on macrophages by setting metabolic commitment for oxidative phosphorylation, which enables macrophages to exhibit anti-inflammatory inclination. Our data elucidate that MSC modification by FGF21 could enhance their therapeutic effect in ALD and may help in the exploration of effective MSCs-based cell therapies for the treatment of ALD.

The Effect of Four Weeks of Swimming Training on Insulin Resistance and Hepatokines in Rats with PCOS

Background: Polycystic Ovary Syndrome (PCOS) is a common endocrine and metabolic disorder in women. Several factors are thought to be affected by exercise, including insulin resistance (IR), FGF-21, and PNPLA3. Objectives: This study aimed to determine the effect of swimming training on IR, FGF-21, and PNPLA-3 gene expression in the liver of rats with PCOS. Methods: A total of 24 adult female Wistar rats were divided into four groups: Healthy control group, PCOS control group, healthy exercise group, and PCOS exercise group. Submaximal endurance swimming training was performed using different water flow rates from seven to 15 liters/minute for four weeks, five days per week for 60 minutes. The IR level and expression of FGF-21 and PNPLA3 genes were measured from the liver tissue. Data was analyzed using SPSS software (version 25) and one-way ANOVA (P &lt; 0.05). Results: Based on the results, a significant difference in the amount of IR (P = 0.001), gene expression of FGF-21 (P = 0.001), and PNPLA-3 (P = 0.001) after four weeks of swimming training was decreased. Conclusions: Four weeks of swimming training improves the metabolic pathway and positively affects patients with PCOS.

Renoprotective effects of genetically proxied fibroblast growth factor 21: Mendelian randomization, proteome-wide and metabolome-wide association study

BackgroundFibroblast growth factor 21 (FGF21) has demonstrated efficacy for reducing liver fat and reversing non-alcoholic steatohepatitis in phase 2 clinical trials. It is also postulated to have anti-fibrotic effects and therefore may be amenable to repurposing for the prevention and treatment of chronic kidney disease (CKD). MethodsWe leverage a missense genetic variant, rs739320 in the FGF21 gene, that associates with magnetic resonance imaging-derived liver fat as a clinically validated and biologically plausible instrumental variable for studying the effects of FGF21 analogs. Performing Mendelian randomization, we ascertain associations between instrumented FGF21 and kidney phenotypes, cardiometabolic disease risk factors, as well as the circulating proteome (Somalogic, 4907 aptamers) and metabolome (Nightingale platform, 249 metabolites). ResultsWe report consistent renoprotective associations of genetically proxied FGF21 effect, including higher glomerular filtration rates (p = 1.9 × 10−4), higher urinary sodium excretion (p = 5.1 × 10−11), and lower urine albumin-creatinine ratio (p = 3.6 × 10−5). These favorable effects translated to lower CKD risk (odds ratio per rs739320 C-allele, 0.96; 95%CI, 0.94–0.98; p = 3.2 × 10−4). Genetically proxied FGF21 effect was also associated with lower fasting insulin, waist-to-hip ratio, blood pressure (systolic and diastolic BP, p < 1.0 × 10−07) and blood lipid (low-density lipoprotein cholesterol, triglycerides and apolipoprotein B, p < 6.5 × 10−24) profiles. The latter associations are replicated in our metabolome-wide association study. Proteomic perturbations associated with genetically predicted FGF21 effect were consistent with fibrosis reduction. ConclusionThis study highlights the pleiotropic effects of genetically proxied FGF21 and supports a re-purposing opportunity for the treatment and prevention of kidney disease specifically. Further work is required to triangulate these findings, towards possible clinical development of FGF21 towards the treatment and prevention of kidney disease.

The effect of FGF21 gene polymorphism (g. 940C/T) on biochemical metabolic parameters in blood serum of holstein cattle

The study examined the effect of polymorphism of the fibroblast growth factor 21 gene (Bos taurus FGF21 g.940 C/T) on the level of FGF21 and biochemical metabolic parameters in blood serum of highproducing cows. DNA genotyping of 148 animals of Holstein cows was performed by a PCR-RFLP method. As a result of genotyping, two FGFC – 0.642 and FGFT – 0.358 alleles as well as two FGFCC – 28.4% (42 animals) and FGFTC – 71.6% (106 animals) genotypes were identified. Individuals with the FGFTT genotype were not identified. The obtained data show that the seroen zyme FGF21 level is statistically significantly higher in cows with the FGF21CC genotype than in cows of the heterozygous genotype by 165.5 pg/ml (28.2%; p &lt; 0.001). Analysis of the association between the polymorphism of the FGF21 gene and the level of fibroblast growth factor 21 suggests that the activity of this enzyme changes depending on the genotype, as a result of which there is a variation in serum biochemical parameters of Holstein cattle.

Phosphorylation of RXRα mediates the effect of JNK to suppress hepatic FGF21 expression and promote metabolic syndrome

The cJun NH2-terminal kinase (JNK) signaling pathway in the liver promotes systemic changes in metabolism by regulating peroxisome proliferator-activated receptor α (PPARα)-dependent expression of the hepatokine fibroblast growth factor 21 (FGF21). Hepatocyte-specific gene ablation studies demonstrated that the Mapk9 gene (encoding JNK2) plays a key mechanistic role. Mutually exclusive inclusion of exons 7a and 7b yields expression of the isoforms JNK2α and JNK2β. Here we demonstrate that Fgf21 gene expression and metabolic regulation are primarily regulated by the JNK2α isoform. To identify relevant substrates of JNK2α, we performed a quantitative phosphoproteomic study of livers isolated from control mice, mice with JNK deficiency in hepatocytes, and mice that express only JNK2α or JNK2β in hepatocytes. We identified the JNK substrate retinoid X receptor α (RXRα) as a protein that exhibited JNK2α-promoted phosphorylation invivo. RXRα functions as a heterodimeric partner of PPARα and may therefore mediate the effects of JNK2α signaling on Fgf21 expression. To test this hypothesis, we established mice with hepatocyte-specific expression of wild-type or mutated RXRα proteins. We found that the RXRα phosphorylation site Ser260 was required for suppression of Fgf21 gene expression. Collectively, these data establish a JNK-mediated signaling pathway that regulates hepatic Fgf21 expression.

β-Hydroxybutyrate upregulates FGF21 expression through inhibition of histone deacetylases in hepatocytes.

Fibroblast growth factor 21 (FGF21) is secreted by hepatocytes as a peptide hormone to regulate glucose and lipid metabolism. FGF21 promotes hepatic ketogenesis and increases ketone body utilization in starvation. Histones are the target molecules of nutrients in regulating hepatic metabolic homeostasis. However, the effect of ketone bodies on FGF21 expression and the involvement of histones in it is not clear yet. The present study observed the effects of β-hydroxybutyrate (β-OHB), the main physiological ketone body, on FGF21 expression in human hepatoma HepG2 cells in vitro and in mice in vivo, and the role of histone deacetylases (HDACs) in β-OHB-regulated FGF21 expression was investigated. The results showed that β-OHB significantly upregulated FGF21 gene expression and increased FGF21 protein levels while it inhibited HDACs’ activity in HepG2 cells. HDACs’ inhibition by entinostat upregulated FGF21 expression and eliminated β-OHB-stimulated FGF21 expression in HepG2 cells. Intraperitoneal injections of β-OHB in mice resulted in the elevation of serum β-OHB and the inhibition of hepatic HDACs’ activity. Meanwhile, hepatic FGF21 expression and serum FGF21 levels were significantly increased in β-OHB-treated mice compared with the control. It is suggested that β-OHB upregulates FGF21 expression through inhibition of HDACs’ activity in hepatocytes.

Overexpression of human OGG1 improves skeletal muscle endurance in mice

8‐oxoguanine glycosylase 1 (OGG1) is a DNA glycosylase that catalyzes the excision of oxidized guanines as part of the base excision repair (BER) DNA repair pathway. While OGG1 has been studied extensively for its role in tumor prevention and neurodegeneration, recent studies have indicated a novel role for this enzyme in maintaining metabolic health. In particular, deletion of OGG1 increased propensity to diet‐ and age‐induced obesity, as well as impaired skeletal muscle dysfunction. In contrast, overexpression of human OGG1 (hOGG1) significantly protected mice from diet‐induced obesity and related metabolic sequelae. Unbiased transcriptomics studies using mice constitutively overexpression OGG1 (Ogg1‐transgenic ‐Ogg1Tg) revealed significant transcriptional changes in skeletal muscle of these mice. Among the most highly induced genes, expression of the myokine fibroblast growth factor‐21(FGF21) was elevated by 9.9 fold in RNA‐Seq analyses. qPCR analysis further confirmed these changes in skeletal muscle without any alterations in the hepatic or cardiac expression of Fgf21. Commensurate with gene expression changes, plasma FGF21 was elevated by 11.2 fold in Ogg1Tg mice relative to WT controls. Conversely, Fgf21 gene expression in skeletal muscle and plasma FGF21 levels were decreased by 25 and 29% respectively in Ogg1‐/‐ mice. Consistent with increased FGF21 activity, phosphorylation of AMPK and its target acetyl CoA carboxylase (ACC), and Ser/Thr phosphorylation of Akt were significantly increased in Ogg1Tg muscle. FGF21 is known to increase expression of PGC‐1α protein. Consistently, Ogg1Tg mice had a 1.6 fold increase in PGC‐1α protein. Given these alterations, we asked if markers of muscle health such as endurance would be altered in Ogg1Tg mice. Interestingly, Ogg1Tg mice displayed a 3.4 fold increase in running capacity, consistent with improved skeletal muscle health in these animals. This improvement in exercise capacity was evident in both young and aged mice and have important implications to the management of age‐related declines in muscle health and DNA repair capacity.

Intermittent protein restriction protects islet β cells and improves glucose homeostasis in diabetic mice

Diabetes is caused by the interplay between genetics and environmental factors, tightly linked to lifestyle and dietary patterns. In this study, we explored the effectiveness of intermittent protein restriction (IPR) in diabetes control. IPR drastically reduced hyperglycemia in both streptozotocin-treated and leptin receptor-deficient db/db mouse models. IPR improved the number, proliferation, and function of β cells in pancreatic islets. IPR reduced glucose production in the liver and elevated insulin signaling in the skeletal muscle. IPR elevated serum level of FGF21, and deletion of the Fgf21 gene in the liver abrogated the hypoglycemic effect of IPR without affecting β cells. IPR caused less lipid accumulation and damage in the liver than that caused by continuous protein restriction in streptozotocin-treated mice. Single-cell RNA sequencing using mouse islets revealed that IPR reversed diabetes-associated β cell reduction and immune cell accumulation. As IPR is not based on calorie restriction and is highly effective in glycemic control and β cell protection, it has promising translational potential in the future.

Effects of feeding frequency on growth performance, feed intake, metabolism and expression of fgf21 in grass carp (Ctenopharyngodon idellus)

Grass carp (Ctenopharyngodon idellus) is one of the most important freshwater cultural species in China. However, obesity, fatty liver and digestive tract inflammation commonly exist in commercial grass carp, which may be due to excessive food and energy intake in daily feeding. Therefore, the feeding strategy should adapt to fish appetite, nutrition requirements and welfare in intensive aquaculture. To investigate the effects of feeding frequency on growth, physiology and metabolism-related fgf21 expression to provide a reference for the selection of feeding strategy, healthy and homogeneous juvenile grass carp (45.2 ± 2.5 g) were randomly divided and adapted to four feeding frequencies of 1, 2, 3 or 4 times/day following satiated feeding for 8 weeks. The growth rate increased with increasing feeding frequency. The hepatosomatic and abdominal fat-somatic indexes were higher in the higher feeding frequency groups, while the gut-somatic index was higher in the low feeding frequency groups (P < 0.05). The actual feeding ration increased from 1.3% to 3.5% with increasing feeding frequency (P < 0.05), and the feed conservation ratio increased from 1.5 to 2.3, but there was no significant difference between 3 and 4 meals/day (P˃0.05). The levels of serum glucose, triglycerides and total cholesterol also increased with increasing feeding frequency, while glycogen levels were higher in the 1 time/day group in both liver and muscle. The activities of digestive enzymes were higher in the high feeding frequency groups. Fgf21 gene expression was relatively low in the low feeding frequency group in all tissues, and the expression levels increased with increasing feeding frequency in the liver and muscle. Overall, the optimal feeding frequency to enhance the growth and health of juvenile grass carp is 3 times/day under apparent satiation.

Evaluation of testicular glycogen storage, FGF21 and LDH expression and physiological parameters of sperm in hyperglycemic rats treated with hydroalcoholic extract of Securigera Securidaca seeds, and Glibenclamide

Structural and physiological changes in sperm and semen parameters reduce fertility in diabetic patients. Securigera Securidaca (S. Securidaca) seed is a herbal medicine with hypoglycemic, antioxidant, and anti-hypertensive effects. The question now is whether this herbal medicine improves fertility in diabetic males. The study aimed to evaluate the effects of hydroalcoholic extract of S. Securidaca seeds (HESS), glibenclamide and a combination of both on fertility in hyperglycemic rats by comparing histological and some biochemical changes in testicular tissue and sperm parameters. The treatment protocol included administration of three doses of HESS and one dose of glibenclamide, as well as treatment with both in diabetic Wistar diabetic rats and comparison of the results with untrated groups. The quality of the testicular tissue as well as histometric parameters and spermatogenesis indices were evaluated during histopathological examination. Epididymal sperm analysis including sperm motility, viability, abnormalities, maturity, and chromatin structure were studied. The effect of HESS on the expression of LDH and FGF21 genes and tissue levels of glycogen, lactate, and total antioxidant capacity in testicular tissue was investigated and compared with glibenclamide. HESS improved sperm parameters in diabetic rats but showed little restorative effect on damaged testicular tissue. In this regard, glibenclamide was more effective than the highest dose of HESS and its combination with HESS enhanced its effectiveness so that histological tissue characteristics and sperm parameters were were comparable to those of healthy rats. The expression level of testicular FGF21 gene increased in diabetic rats, which intensified after treatment with HESS as well as glibenclamide. The combination of HESS and glibenclamide restored the expression level of testicular LDH gene, as well as tissue storage of glycogen, lactate and LDH activity, and serum testosterone to the levels near healthy control. S. Securidaca seeds can be considered as an effective supplement in combination with hypoglycemic drugs to prevent infertility complications in diabetes.

115-LB: Liver-Derived FGF21 Mediates the Promoting Effect of Glucagon Receptor Antagonism on Beta-Cell Regeneration in Type 2 Diabetic Mice

Objective: Based on the clear role for glucagon in the pathogenesis of diabetes, glucagon-blocking therapies have been pursued as a therapeutic strategy for this disease. Here, we used REMD 2.59, a human antagonistic glucagon receptor (GCGR) monoclonal antibody (mAb), to clarify the effects of GCGR mAb in promoting pancreatic β cell regeneration in type 2 diabetes (T2D), and its potential mechanism. Methods: GCGR mAb was administrated weekly for 4 weeks in db/db mice and HFD/STZ-induced T2D mice, including different lineage-tracing mice. The plasma insulin and glucagon were determined by using ELISA. The evaluation of islet morphology was performed with immunofluorescent analysis. GCGR mAb was also treated in the systemic Fgf21 gene knockout (Fgf21-/-) and hepatocyte-specific Fgf21 gene knockout (Fgf21Hep-/-) T2D mice. Results: Treatment with GCGR mAb lowered blood glucose, improved glucose tolerance, and elevated plasma glucagon and insulin levels in both db/db mice and HFD/STZ-induced T2D mice. The β cell dedifferentiation as indicated by β cell lineage-tracing was blocked by GCGR mAb. The β cell proliferation as indicated by insulin+ and BrdU+ cells was boosted by GCGR mAb. The α-to-β cell conversion, as evaluated by glucagon+ insulin+ cells and confirmed by α cell lineage-tracing, was facilitated by GCGR mAb. After GCGR mAb treatment, some insulin+ cells were located in the duct region or even colocalized with duct cell markers, suggestive of duct-derived β cell neogenesis that was also verified by Ngn3+ cell lineage-tracing. Notably, GCGR mAb could still improve glucose tolerance and increase β cell mass, but these effects were attenuated in Fgf21-/- and Fgf21Hep-/- T2D mice compared with WT T2D mice. Conclusions: GCGR mAb promotes β cell regeneration via inhibiting β cell dedifferentiation and promoting β cell self-replication, α-to-β cell conversion and duct-derived β cell neogenesis in T2D mice, which is partly mediated by liver-derived FGF21. Disclosure X. Cui: None. T. Wei: None. J. Feng: None. J. Yang: None. H. Yan: Board Member; Self; REMD Biotherapeutics, Other Relationship; Spouse/Partner; REMD Biotherapeutics. R. Wei: None. T. Hong: Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp &amp; Dohme Corp., Novo Nordisk, Sanofi. Funding National Natural Science Foundation of China (81830022)

Dietary Patterns and Their Associations With the FTO and FGF21 Gene Variants Among Emirati Adults.

Purpose: To examine the dietary patterns and their associations with the FTO and FGF21 gene variants among Emirati adults.Methods: Using a cross-sectional design, healthy adult male and female Emiratis (n = 194) were recruited from primary health care centers in Sharjah, UAE. Participants completed a 61-item semi-quantitative food frequency questionnaire. In addition, a saliva sample was obtained for the genetic analysis. Genotyping was performed for FTOrs9939609(A>T), FTOrs9930506(A>G), FGF21 rs838133 (A > G), and FGF21 rs838145 (A > G). Dietary patterns were derived using the principal component analysis. Logistic regression analyses were used to examine the association of dietary patterns with genetic variants.Results: Three dietary patterns were identified: “Western”: consisting of fast food, sweets, and processed meat; “Traditional Emirati” rich in vegetables, traditional Emirati-mixed-dishes and whole dairy; while whole grains, low-fat dairy, and bulgur were components of the “Prudent” pattern. Subjects carrying the A allele of the FTO rs9939609 were 2.41 times more likely to adhere to the Western pattern compared to subjects with genotype TT (OR:2.41; 95%CI:1.05–5.50). Compared with subjects with A/A, those carrying the G allele of the FTO rs9930506 were more likely to follow a Western diet (OR: 2.19; 95%CI: 1.00–4.97). Participants carrying the risk allele (A) of the FGF21 rs838133 were twice more likely to adhere to the Traditional pattern as compared to subjects with genotype GG (OR: 1.9, 95%CI: 1.01–3.57).Conclusions: The findings of this study suggested associations among specific FTO and FGF21 gene variants with dietary patterns among Emirati adults. These findings could be used to inform evidence-based targeted nutrition preventive recommendations, especially those aiming to limit intake of western type foods.

The Effect of Interval Training and Consuming Fenugreek Seed Extract on FGF-21 and VEGF Gene Expression in Patients With Coronary Artery Diseases

Aims: A high-fat diet, smoking, and a sedentary lifestyle are the major causes of Coronary Artery Disease (CAD). This study aimed to explore the effect of interval training and the consumption of fenugreek seed extract on FGF-21 and VEGF gene expression among patients with CAD. Methods &amp; Materials: The present quasi-experimental study was conducted on a sample of 32 male patients with CAD, aged between 55 and 65 years. They were randomly divided into four groups: control, training only, fenugreek only, and training + fenugreek. The training program consisted of eight weeks of interval running, three sessions per week with an intensity of 55% and 65% of heart rate reserve, with a gradually increasing intensity. Subjects consumed 10 mg/kg of fenugreek extract daily. Real-time PCR was used to measure the expression of FGF-21 and VEGF genes. Findings: The results showed that the mean expression ratios of FGF-21 in training only, fenugreek only, and training + fenugreek groups were significantly higher than the control group (P&lt;0.0001). The fenugreek + training group had a greater significant increase (P&lt;0.0001) more than the training + fenugreek group. Moreover, the mean Coefficient of Variation (CV) of VEGF gene expression was significantly increased more than that in the training group (P&lt;0.0001), fenugreek group (P=0.0004), and the training + fenugreek group (P&lt;0.0001), compared to the control group. The fenugreek + training group had a greater and more significant increase than the training only (P=0.0181) and the fenugreek only groups (P&lt;0.0495). Conclusion: The results showed that a combination of interval training and consumption of fenugreek seed extract increased the CV of FGF-21 and VEGF gene expression and thus, have beneficial effects on the angiogenesis pathway in patients with CADs

Triclosan leads to dysregulation of the metabolic regulator FGF21 exacerbating high fat diet-induced nonalcoholic fatty liver disease.

Triclosan (TCS), employed as an antiseptic and disinfectant, comes into direct contact with humans through a plethora of consumer products and its rising environmental release. We have demonstrated that TCS promotes liver tumorigenesis in mice, yet the biological and molecular mechanisms by which TCS exerts its toxicity, especially in early stages of liver disease, are largely unexplored. When mice were fed a high-fat diet (HFD), we found that fatty liver and dyslipidemia are prominent early signs of liver abnormality induced by TCS. The presumably protective HFD-induced hepatic expression of the metabolic regulator fibroblast growth factor 21 (FGF21) was blunted by TCS. TCS-altered Fgf21 expression aligned with aberrant expression of genes encoding metabolic enzymes manifested as profound systemic metabolic changes that disturb homeostasis of amino acids, fatty acids, and glucose. Using a type 1 diabetic animal model, TCS potentiates and accelerates the development of steatohepatitis and fibrosis, accompanied by increased levels of hepatic lipid droplets and oxidative stress. Analysis of fecal samples revealed that HFD-fed mice exhibited a reduction in fecal species richness, and that TCS further diminished microbial diversity and shifted the bacterial community toward lower Bacteriodetes and higher Firmicutes, resembling changes in microbiota composition in nonalcoholic steatohepatitis (NASH) patients. Using reverse-genetic approaches, we demonstrate that, along with HFD, TCS induces hepatic steatosis and steatohepatitis jointly regulated by the transcription factor ATF4 and the nuclear receptor PPARα, which participate in the transcriptional regulation of the Fgf21 gene. This study provides evidence linking nutritional imbalance and exposure to TCS with the progression of NASH.

Growth of beef cattle as prediction for meat production: A review

Growth of beef cattle as prediction for meat production: A review

370-OR: Hepatic FGF21 Expression Is Under the Regulation of the Canonical Wnt Signaling Pathway

The metabolic hormone FGF-21 is mainly produced and released from the liver in response to nutritional stresses such as starvation, alcohol or ketogenic diet consumption. Body weight lowering and insulin signaling sensitization effects of FGF-21 and its analogues have been demonstrated in animal models or in human subjects. We show here that hepatic FGF-21 mRNA and FGF-21 protein levels were reduced in male LTCFDN, a transgenic mouse line in which canonical Wnt signaling cascade is functionally attenuated due to the expression of dominant negative transcription factor TCF7L2 in the liver, and the reduction is not associated with reduced expression of PPARα, a key transactivator of FGF-21. Furthermore, starvation-induced plasma FGF-21 elevation was also attenuated in male LTCFDN mice. Utilizing mouse primary hepatocytes, we found that FGF-21 mRNA and FGF-21 protein expression can be increased by Wnt-3a or LiCl treatment. Two evolutionarily conserved TCF binding motifs (TCFB) were then located within the mouse FGF-21 gene promoter. Luciferase and ChIP results suggest that one of them is responsible for β-cat/TCF mediated activation on FGF-21 transcription.It has been shown recently that in mouse brain tanycytes, FGF-21 secretion can be induced by palmitate treatment. We found that in mouse primary hepatocytes, palmitate but not oleate treatment increased expression of the Wnt target gene Ccnd1, which encodes cyclin D1. Our observations hence suggest that Wnt signaling cascade is involved in hepatic FGF-21 production and secretion, and the positive regulation is likely independent of fibrate/PPARα-mediated induction. Investigations on this novel hepatic signaling axis will strengthen our knowledge on the physiologically significant hormone FGF-21, leading to novel therapeutic avenues in treating impaired metabolism. Disclosure Y. Badakhshi: None. W. Shao: None. L. Tian: None. T. Jin: None. Funding Canadian Institutes of Health Research (PJT159735)

SAT-652 Increased Fibroblast Growth Factor 21 Protein Expression via in Vivo Delivery of a Liver-Specific Expression Plasmid

Fibroblast growth factor 21 (FGF21) is an important liver-secreted hormone that activates thermogenesis in white and brown fat deposits. In various models of obesity, FGF21 administration consistently facilitates weight loss and improved metabolic function. Several FGF21 variants, which have been engineered to improve protein stability and solubility in solutions containing preservatives, are currently in human clinical trials. In addition, in vivo FGF21 gene therapy using viral vector is being explored as an alternative therapeutic approach. In this study, we present a simpler method of in vivo FGF21 gene therapy, in which liver-specific delivery of an unpackaged plasmid construct expressing an HA-tagged FGF21 protein increases de novo hepatic FGF21 production and secretion in mice. Our data show that FGF21 protein expression can be successfully restored into the livers of FGF21 conditional knockout mice for at least two weeks after a single tail vein injection with the expression plasmid, and that the HA-tagged protein is secreted and readily detectable in serum. In wild-type C57BL6/J mice, in vivo plasmid delivery significantly increased hepatic FGF21 protein 2.3-fold after two weeks, and was associated with reduced body mass and a 14% reduction in fasting serum glucose. In addition, elevated hepatic FGF21 levels correlated with a 27% decrease in the ratio of fat to body mass, visibly smaller subcutaneous and visceral white fat adipocytes, and a 3.3-fold increase in uncoupling protein 1-dependent mitochondrial respiration in the white fat. Together, these data suggest that in vivo plasmid delivery may potentially be an effective strategy for promoting hepatic FGF21 expression in models of obesity. We are currently testing this hypothesis with experiments in high-fat diet-challenged mice.

Molecular description of fibroblast growth factor and mechanisms by which fibroblast growth factor-21 mediating biological actions and acting as a biologic biomarker of cardiovascular diseases

Fibroblast growth factor (FGF) family members are mostly secreted as signaling proteins with diverse functions in development and metabolism. FGFs can be classified as intracellular, paracrine, and endocrine FGFs by their action mechanisms. FGF-21 is a novel member of endocrine FGF subfamily with pleotropic actions. Recent findings indicate that FGF-21 can act as a cardiomyokine; that is, it is produced by cardiac cells and acts in an autocrine manner on the heart itself. The heart is sensitive to the effects of FGF-21, both systemic and locally generated, owing to the expression in cardiomyocytes of β-Klotho, the key coreceptor known to confer specific responsiveness to FGF-21 action. It has been shown to exert cardioprotective effects in against cardiac hypertrophy, myocardial infarction, cardiac inflammation, cardiac ischemia-reperfusion injury, diabetic cardiomyopathy, and oxidative stress. It also promotes energy supply to the heart through fatty acid β-oxidation. Intracellular mechanisms involving peroxisome proliferator-activated receptor α and sirtunin 1 mediate transcriptional regulation of the FGF-21 gene in response to exogenous stimuli. This review explores the molecular mechanism by which FGF-21 provides cardioprotection.