Bone Morphogenetic Protein 9 Protects Against Myocardial Infarction by Improving Lymphatic Drainage Function and Triggering DECR1-Mediated Mitochondrial Bioenergetics.

BACKGROUND: BMP9 (bone morphogenetic protein 9) is a member of the TGF-ß (transforming growth factor ß) family of cytokines with pleiotropic effects on glucose metabolism, fibrosis, and lymphatic development. However, the role of BMP9 in myocardial infarction (MI) remains elusive. METHODS: The expressional profiles of BMP9 in cardiac tissues and plasma samples of subjects with MI were determined by immunoassay or immunoblot. The role of BMP9 in MI was determined by evaluating the impact of BMP9 deficiency and replenishment with adeno-associated virus-mediated BMP9 expression or recombinant human BMP9 protein in mice. RESULTS: We show that circulating BMP9 and its cardiac levels are markedly increased in humans and mice with MI and are negatively associated with cardiac function. It is important to note that BMP9 deficiency exacerbates left ventricular dysfunction, increases infarct size, and augments cardiac fibrosis in mice with MI. In contrast, replenishment of BMP9 significantly attenuates these adverse effects. We further demonstrate that BMP9 improves lymphatic drainage function, thereby leading to a decrease of cardiac edema. In addition, BMP9 increases the expression of mitochondrial DECR1 (2,4-dienoyl-CoA reductase 1), a rate-limiting enzyme involved in ß-oxidation, which, in turn, promotes cardiac mitochondrial bioenergetics and mitigates MI-induced cardiomyocyte injury. Moreover, DECR1 deficiency exacerbates MI-induced cardiac damage in mice, whereas this adverse effect is restored by the treatment of adeno-associated virus-mediated DECR1. Consistently, DECR1 deletion abrogates the beneficial effect of BMP9 against MI-induced cardiomyopathy and cardiac damage in mice. CONCLUSIONS: These results suggest that BMP9 protects against MI by fine-tuning the multiorgan cross-talk among the liver, lymph, and the heart.

Myocardial infarction accelerates the progression of MASH by triggering immunoinflammatory response and induction of periosti.

Patients with metabolic dysfunction-associated steatotic liver disease (MASLD), especially advanced metabolic dysfunction-associated steatohepatitis (MASH), have an increased risk of cardiovascular diseases (CVDs). Whether CVD events will, in turn, influence the pathogenesis of MASLD remains unknown. Here, we show that myocardial infarction (MI) accelerates hepatic pathological progression of MASLD. Patients with MASLD who experience CVD events after their diagnosis exhibit accelerated liver fibrosis progression. MI promotes hepatic fibrosis in mice with MASH, accompanied by elevated circulating Ly6Chi monocytes and their recruitment to damaged liver tissues. These adverse effects are significantly abrogated when deleting these cells. Meanwhile, MI substantially increases circulating and cardiac periostin levels, which act on hepatocytes and stellate cells to promote hepatic lipid accumulation and fibrosis, finally exacerbating hepatic pathological progression of MASH. These preclinical and clinical results demonstrate that MI alters systemic homeostasis and upregulates pro-fibrotic factor production, triggering cross-disease communication that accelerates hepatic pathological progression of MASLD.

Adipose c-Jun NH2-terminal kinase promotes angiotensin II-induced and deoxycorticosterone acetate salt-induced hypertension and vascular dysfunction by inhibition of adiponectin production and activation of SGK1 in mice.

BACKGROUND: Adipose c-Jun NH2-terminal kinase 1/2 (JNK1/2) is a central mediator involved in the development of obesity and its complications. However, the roles of adipose JNK1/2 in hypertension remain elusive. Here we explored the role of adipose JNK1/2 in hypertension. METHODS AND RESULTS: The roles of adipose JNK1/2 in hypertension were investigated by evaluating the impact of adipose JNK1/2 inactivation in both angiotensin II (Ang II)-induced and deoxycorticosterone acetate (DOCA) salt-induced hypertensive mice. Specific inactivation of JNK1/2 in adipocytes significantly alleviates Ang II-induced and DOCA salt-induced hypertension and target organ damage in mice. Interestingly, such beneficial effects are also observed in hypertensive mice after oral administration of JNK1/2 inhibitor SP600125. Mechanistically, adipose JNK1/2 acts on adipocytes to reduce the production of adiponectin (APN), then leads to promote serum and glucocorticoid-regulated kinase 1 (SGK1) phosphorylation and increases epithelial Na + channel α-subunit (ENaCα) expression in both renal cells and adipocytes, respectively, finally exacerbates Na + retention. In addition, chronic treatment of recombinant mouse APN significantly augments the beneficial effects of adipose JNK1/2 inactivation in DOCA salt-induced hypertension. By contrast, the blood pressure-lowering effects of adipose JNK1/2 inactivation are abrogated by adenovirus-mediated SGK1 overexpression in Ang II -treated adipose JNK1/2 inactivation mice. CONCLUSION: Adipose JNK1/2 promotes hypertension and targets organ impairment via fine-tuning the multiorgan crosstalk among adipose tissue, kidney, and blood vessels.

Increased circulating FGF21 level predicts the burden of metabolic demands and risk of vascular diseases in adults with type 2 diabetes.

OBJECTIVES: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by chronic hyperglycemia and metabolic stress, involved in the stepwise development of cardiovascular complications. Fibroblast growth factor 21 (FGF21) is a novel hepatokine involved in regulating glucose and lipid metabolism, and has been linked to the prediction, treatment, and improvement of prognosis in multiple cardiovascular diseases (CVDs). The aim of this study is to explore the relationship between FGF21 levels and vascular diseases (VDs) including carotid atherosclerosis (CAS) and hypertension (HP) in patients with T2DM. METHODS: Baseline serum FGF21 was determined in a cross-sectional study of 701 patients with T2DM and 258 healthy control. RESULTS: The morbidity of CAS was increased in T2DM patients with HP as compared with those without (p < 0.001). The average serum FGF21 level of healthy was [123.9 (67.2-219.3)]. Baseline FGF21 was significantly higher in those who developed CAS or HP than in those who did not [305.9 (177.2-508.4) vs. 197.2 (129.7-308.3) pg/mL, p < 0.001]. In addition, an elevated serum FGF21 was observed in T2DM patients with HP and CAS than that of T2DM patients with CAS or HP [550.5 (312.6-711.3) vs. 305.9 pg/mL, p < 0.001]. Serum FGF21 levels were positively correlated with body mass index and carotid intima media thicknes (p < 0.05), the association remained significant after adjusting for age and T2DM duration. Furthermore, the multinomial logistic regression showed that serum FGF21 was independently associated with CAS and HP in patients with T2DM after adjustment for demographic and traditional VDs risk factors (p < 0.001). CONCLUSIONS: Baseline FGF21 is elevated in VDs during diabetes, changes of serum FGF21 levels were appropriately matched to metabolic stress. FGF21can be used as an independent predictor for diagnosing VDs and predicting prognosis.

2-Geranyl-1-methoxyerythrabyssin II alleviates lipid accumulation and inflammation in hepatocytes through AMPK activation and AKT inhibition.

A growing proportion of the global adult and pediatric populations are currently affected by nonalcoholic steatohepatitis (NASH), leading to rising rates of liver fibrosis and hepatocellular carcinoma without effective pharmacotherapy. Here, we investigated whether 2-geranyl-1-methoxyerythrabyssin II (GMET), isolated from Lespedeza bicolor, could alleviate lipid accumulation and inflammatory responses in a NASH model. GMET exhibited potent in vitro and in vivo effects against lipid accumulation and attenuated inflammatory responses without cytotoxicity. Mechanistically, GMET inhibits acetyl-CoA carboxylase (ACC), sterol regulatory element-binding proteins-1c (SREBP1), and mammalian target of rapamycin (mTOR), and activates PPARα by activating AMP-activated kinase (AMPK), leading to the alleviation of lipid accumulation. In addition, GMET suppresses the NF-κB pathway by activating AMPK and inhibiting the activated protein kinase B (AKT)/IκB-kinase (IKK) pathway, leading to the inhibition of the inflammatory response in hepatocytes. All these protective effects of GMET on lipid accumulation and inflammation in vivo and in vitro were largely abolished by co-treatment with dorsomorphin, an AMPK inhibitor. In conclusion, GMET alleviated lipid accumulation and inflammation to preserve normal hepatocyte function in steatohepatitis. Thus, GMET is a novel potential multi-targeting compound to improve steatohepatitis.

Fibroblast growth factor 21 resistance is associated with body shape in patients with type 2 diabetes complicating hypertension.

Objectives: Obesity, especially abdominal obesity, increases the prevalence of metabolic and cardiovascular disease (CVD). Fibroblast growth factor 21 (FGF21) has been identified as a critical regulator playing a therapeutic role in diabetes and its complications. This study aims to evaluate the relationship between serum FGF21 levels and body shape parameters in patients with hypertension (HP) and type 2 diabetes mellitus (T2DM). Methods: Serum FGF21 levels were determined in 1,003 subjects, including 745 patients with T2DM, and 258 individuals were selected as a healthy control in this cross-sectional study. Results: Serum FGF21 levels were significantly higher in T2DM patients with HP than those without [534.9 (322.6-722.2) vs. 220.65 (142.8-347.55) pg/ml, p < 0.001], and levels in both of these two groups were significantly increased compared with that of healthy control [123.92 (67.23-219.32) pg/ml, all p < 0.001]. These differences were also observed in body shape parameters, including weight, waistline, body mass index (BMI), body shape index (ABSI), and the percentage of abdominal obesity. Serum FGF21 levels in T2DM patients were positively correlated with body shape parameters, including weight, waistline, neck circumference, BMI, ABSI, percent of abdominal obesity, and triglyceride, while negatively with estimated glomerular filtration rate (all p < 0.01). The significance remained stable when adjusted for age and T2DM duration. In addition, both serum FGF21 concentrations and waistline were independently associated with HP in T2DM patients after the adjustment for risk factors (all p < 0.05). ROC analysis for FGF21 levels of 745 patients with T2DM identified 411.33 pg/ml as an optimal cut-off point to predict HP, with a sensitivity and specificity of 66.0% and 84.9%, respectively. Conclusions: FGF21 resistance occurs in patients of HP in T2DM, and positively correlates with body shape parameters (especially waistline and BMI). High levels of FGF21 may be a compensatory reaction to offset HP.

Extracellular status of thrombospondin-2 in type 2 diabetes mellitus and utility as a biomarker in the determination of early diabetic kidney disease.

OBJECTIVE: Thrombospondin-2 (TSP-2) is a multifunctional matricellular glycoprotein correlated with glucose homeostasis, insulin sensitivity, and estimated glomerular filtration rate. Investigation of the association of TSP-2 with type 2 diabetes mellitus (T2DM) and the potential diagnostic value of serum TSP-2 for detecting early diabetic kidney disease (DKD) is needed. RESEARCH DESIGN AND METHODS: An enzyme-linked immunosorbent assay was used for detection serum TSP-2 levels in 494 Chinese T2DM subjects. The protein expression of TSP-2 in the kidney and other tissues were tested by western blotting. RESULTS: Serum TSP-2 levels in T2DM subjects were significantly higher than in healthy individuals. Serum TSP-2 correlated positively with triglycerides, serum uric acid, creatinine, platelets, and urinary albumin-to-creatinine ratio (UACR), but negatively with estimated glomerular filtration rate, after adjusting for age, sex, and T2DM duration. Logistic regression analysis demonstrated an independent association between serum TSP-2 and early DKD. Furthermore, the high UACR identified at risk of early DKD increased significantly from 0.78 (95%CI 0.73-0.83) to 0.82 (95%CI 0.77-0.86, p < 0.001) when added to a clinical model consisting of TSP-2 and age. In db/db mice, serum TSP-2 levels were elevated. TSP-2 expression was markedly increased in the kidney tissue compared with that in db/m and m/m mice. Furthermore, serum TSP-2 expression correlated well with UACR in mice. CONCLUSIONS: TSP-2 is a novel glycoprotein associated with early DKD in patients with T2DM. The paradoxical increase of serum TSP-2 in T2DM individuals may be due to a compensatory response to chronic inflammatory and renal vascular endothelial growth, warranting further investigation.

Serum Lipocalin-2 Levels Are Increased and Independently Associated With Early-Stage Renal Damage and Carotid Atherosclerotic Plaque in Patients With T2DM.

Objectives: Diabetic nephropathy (DN), one of the major complications of diabetes mellitus, is the major cause of end-stage renal failure that finally increases the risk of cardiovascular disease and mortality. The aim of this study is to explore the relationship between serum lipocalin-2 (LCN-2) levels and DN and carotid atherosclerotic plaque (CAP) in patients with type 2 diabetes mellitus (T2DM). Methods: We have performed a prospective study of 749 T2DM patients with or without DN. Blood samples were collected and used to test serum LCN-2 levels, renal function, as well as biochemical parameters. CAP in these subjects was determined by ultrasonography. Results: In these 749 subjects with T2DM, an increased morbidity of CAP was observed in T2DM patients with DN as compared with those without this complication (P < 0.05). Interestingly, serum LCN-2 levels were significantly increased in T2DM patients with DN or CAP compared with T2DM alone [97.71 (71.49-130.13) vs. 77.29 (58.83-115.05) ng/ml, P < 0.001]. In addition, serum LCN-2 levels in T2DM patients with DN and CAP were significantly higher than that of T2DM patients with DN or CAP [131.37 (101.43-182.04) vs. 97.71(71.49-130.13) ng/ml, P < 0.001]. Furthermore, serum LCN-2 levels were positively correlated with hemoglobin A1c, systolic blood pressure, hypertension, CAP, and DN, as well as renal function factors including uric acid, creatinine, the estimated glomerular filtration rate, and urinary albumin-to-creatinine ratio, respectively (P < 0.05), but negatively correlated with HDL-c (P < 0.05). The multinomial logistic regression analysis showed that serum LCN-2 was independently associated with DN and CAP in patients with T2DM after the adjustment for risk factors (P < 0.001). Conclusions: Early-stage renal damage is a risk factor associated with the incidence of CAP in patients with T2DM. Serum LCN-2 is significantly increased and associated with early-stage renal damage and the incidence of CAP in patients with T2DM.

Serum FGF21 Levels Predict the MACE in Patients With Myocardial Infarction After Coronary Artery Bypass Graft Surgery.

Objectives: Prognosis evaluation in myocardial infarction (MI) patients with major adverse clinical events (MACE) who have undergone coronary artery bypass graft (CABG) is greatly important to identify high-risk patients. Elevated metabolic hormone fibroblast growth factor 21 (FGF21) is associated with the risk of MI. The aim of this study is to assess the relationship between FGF21 and the incidence of MACE in patients with MI after CABG surgery. Methods: Patients with three-vessel disease who were scheduled for first-time isolated CABG were enrolled in this project and underwent to evaluate the incidence of MACE during 48 h after CABG surgery, as well as to collect serum samples for FGF21 levels in both preoperative- and postoperative-CABG (pre-CABG and post-CABG). Results: A total of 265 patients with MI undergoing CABG were enrolled in this study, 21 patients experienced MACE during the 48 h after CAGB surgery. Serum FGF21 levels of patients with MACE at post-CABG were significantly higher than that in patients without MACE [553.7 (433.6) vs. 291.7 (334.4), p < 0.001]. Furthermore, among 81 individuals of these 265 patients, a lower level of FGF21 in preoperative-CABG (pre-CABG) and a higher level of FGF21 at postoperative-CABG (post-CABG) were observed in MI patients with MACE as compared to those without MACE respectively [ (275.0 (260.4) vs. 410.3 (420.7), p = 0.049; 550.7 (519.9) vs. 370.6 (441.2), p = 0.031]. In addition, serum FGF21 levels of MI patients with MACE at post-CABG were significantly increased compared with the baseline levels in pre-CABG [550.7 (519.9) vs.275.0 (260.4) p < 0.001]. However, these profiles were not observed in patients without MACE [410.3 (420.7) vs. 370.6 (441.2), p=0.2137]. Logistic regression analysis demonstrated that both serum FGF21 and CK-MB levels at post-CABG were independently associated with the incidence of MACE in patients with MI after CABG surgery. Finally, ROC analysis for FGF21 levels of 265 MI patients at post-CABG identified 455.4 pg/ml as an optimal cut-off value to predict MACE, with a sensitivity and specificity of 91.7 and 68.4% respectively. Conclusion: Serum FGF21 levels at post-CABG are independently associated with the incidence of MACE in patients with MI who have undergone CABG. Measurement of FGF21 may help distinguish patients with MI at a high risk of MACE after CABG surgery.

Ginsenoside Rh2 attenuates CDAHFD-induced liver fibrosis in mice by improving intestinal microbial composition and regulating LPS-mediated autophagy.

BACKGROUND: Nowadays, liver diseases are threatening more and more people all over the world and one of the main causes is liver fibrosis. However, there is no effective way to reverse liver fibrosis. PURPOSE: To investigate whether ginsenoside Rh2 (G-Rh2) can alleviate liver fibrosis and elucidate its underlying mechanism. METHODS: In vivo and in vitro methods were adopted in this research. Choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) was used to feed mice to induce liver fibrosis, and HSC-T6 cells were used to establish an LPS-induced model of liver fibrosis. Through histopathological staining, hematoxylin-eosin (H&E) staining, western blot analysis, intestinal bacteria 16SrRNA sequencing, and other technical means, the research explored whether G-Rh2 possesses anti-fibrotic activity. RESULTS: G-Rh2 could notably alleviate CDAHFD-induced liver fibrosis in mice. In particular, it could alleviate liver injury and reduce plasma lipopolysaccharide (LPS) levels. Additionally, G-Rh2 could repair intestinal injury as well as regulate intestinal microbial diversity and composition. HSC-T6 cells could be activated and autophagy could be induced further by LPS in vitro. After being treated with G-Rh2, autophagy was restrained and activation of hepatic stellate cells (HSCs) was controlled. Deeper research showed that G-Rh2 restrained the activation of HSCs via stimulating the AKT-mTOR signaling pathway, restraining autophagy. CONCLUSION: The results of our studies clearly suggest that G-Rh2 repairs intestinal injury, improves intestinal microbial composition, reduces plasma LPS levels, and activates the AKT-mTOR signaling pathway to restrain LPS-mediated autophagy, thus playing an important role in anti-hepatic fibrosis. G-Rh2 was found to have the potential to effectively alleviate liver fibrosis.

Ginsenoside Rg2 Ameliorating CDAHFD-Induced Hepatic Fibrosis by Regulating AKT/mTOR-Mediated Autophagy.

Ginsenoside Rg2 (G-Rg2) in the rhizome of Panax ginseng can modify lipid accumulation, oxidative stress, and apoptosis in the liver induced by a high-fat diet. This research adds to this by assessing the potential antifibrosis effect of G-Rg2 (including possible mechanisms). G-Rg2 significantly improved pathological changes in liver tissue induced by a choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD), it inhibited serum transaminase, plasma lipopolysaccharide, and liver hydroxyproline levels; it inhibited TGF-ß1, α-SMA, and COL1A1 expression, it activated the AKT/mTOR signal pathway, and it inhibited liver expression of autophagy-related proteins. The in vitro experiments showed that G-Rg2 also restored the autophagy flux impairment induced by oleic acid and inhibited TGF-ß1 expression by promoting p62 degradation in hepatocytes. In hepatic stellate (HSC-T6) cells, G-Rg2 reversed lipopolysaccharide-induced activation through the AKT/mTOR signaling pathway, inhibiting autophagy. Thus, G-Rg2 ameliorates CDAHFD-induced liver fibrosis and lipopolysaccharide-induced HSC-T6 cell activation by inhibiting AKT/mTOR-mediated autophagy.

FGF21 alleviates acute liver injury by inducing the SIRT1-autophagy signalling pathway.

Liver injury can lead to different hepatic diseases, which are the mainly causes of high global mortality and morbidity. Autophagy and Sirtuin type 1 (SIRT1) have been shown protective effects in response to liver injury. Previous studies have showed that Fibroblast growth factor 21 (FGF21) could alleviate acute liver injury (ALI), but the mechanism remains unclear. Here, we verified the relationship among FGF21, autophagy and SIRT1 in carbon tetrachloride (CCl4 )-induced ALI. We established CCl4 -induced ALI models in C57BL/6 mice and the L02 cell line. The results showed that FGF21 was robustly induced in response to stress during the development of ALI. After exogenous FGF21 treatment in ALI models, liver damage in ALI mice was significantly reduced, as well as serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Consistently, FGF21 also greatly reduced the levels of ALT, AST, pro-inflammatory cytokines interleukin 6 (IL6) and tumour necrosis factor-alpha (TNFα) in ALI cell lines. Mechanistically, exogenous FGF21 treatment efficiently upregulated the expression of autophagy marker microtubule-associated protein light chain-3 beta (LC3 II) and autophagy key molecule coiled-coil myosin-like BCL2-interacting protein (Beclin1), which was accompanied by alleviating hepatotoxicity in CCl4 -treated wild-type mice. Then, we examined how FGF21 induced autophagy expression and found that SIRT1 was also upregulated by FGF21 treatment. To further verify our results, we constructed an anti-SIRT1 lentit-RNAi to inhibit SIRT1 expression in mice and L02 cells, which reversed the protective effect of FGF21 on ALI. In summary, these results indicate that FGF21 alleviates ALI by enhancing SIRT1-mediated autophagy.

Identification of exosomal mRNA, lncRNA and circRNA signatures in an osteoarthritis synovial fluid-exosomal study.

AIMS: Osteoarthritis (OA) is a common degenerative disease that is pathologically characterized by destruction of the joint matrix and reduction of articular chondrocytes, resulting in joint deformity and motor dysfunction. However, the molecular mechanisms governing this pathology have not been elucidated to date. METHODS: In this study, we determined the expression levels of lncRNAs, circRNAs, and mRNAs extracted from synovial exosomes of OA and control patients. A network of circRNA/lncRNA-miRNA-mRNA interactions was established using MiRanda and TargetScan software to explore OA pathogenesis. The exosomal lncRNA, circRNA and mRNA expression profiles of the OA and control groups were analysed using LC human competing endogenous RNA (ceRNA) microarrays. The differentially expressed genes were analysed to determine their potential roles in the pathogenesis of OA by bioinformatic analysis. RESULTS: There were 52 mRNAs, 196 lncRNAs and 98 circRNAs differentially expressed in synovial exosomes between osteoarthritis synovial and the control group. The final ceRNA network of lncRNAs and circRNAs exhibited a complex interaction between ncRNA and mRNA related to OA pathological mechanisms. An intersection analysis of the ceRNA network showed that 22 miRNAs, 45 lncRNAs, and 34 circRNAs enriched in the PI3K/Akt and autophagy pathways correlated with 7 mRNAs and may play important roles in OA pathological mechanisms. CONCLUSION: Our work analysed mRNA/lncRNA/circRNA expression and displayed the ceRNA network of lncRNAs and circRNAs to profile the pathogenesis of OA in synovial exosomes. The results of this study may help to elucidate the pathogenesis of OA and may provide important references for further research attempting to identify more effective targets for the diagnosis and therapy of OA.

Fibroblast growth factor 21 alleviates acute pancreatitis via activation of the Sirt1-autophagy signalling pathway.

Fibroblast growth factor 21 (FGF21), a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity, alleviates the process of acute pancreatitis (AP). However, its mechanism remains elusive. The pathological and physiological characteristics of FGF21 are observed in both patients with AP and cerulein-induced AP models, and the mechanisms of FGF21 in response to AP are investigated by evaluating the impact of autophagy in FGF21-treated mice and cultured pancreatic cells. Circulating levels of FGF21 significantly increase in both AP patients and cerulein-induced AP mice, which is accompanied by the change of pathology in pancreatic injury. Replenishment of FGF21 distinctly reverses cerulein-induced pancreatic injury and improves cerulein-induced autophagy damage in vivo and in vitro. Mechanically, FGF21 acts on pancreatic acinar cells to up-regulate Sirtuin-1 (Sirt1) expression, which in turn repairs impaired autophagy and removes damaged organs. In addition, blockage of Sirt1 accelerates cerulein-induced pancreatic injury and weakens the regulative effect in FGF21-activated autophagy in mice. These results showed that FGF21 protects against cerulein-induced AP by activation of Sirtuin-1-autophagy axis.

SIRT1 Mediates Effects of FGF21 to Ameliorate Cisplatin-Induced Acute Kidney Injury.

Acute kidney injury (AKI) is a common complication in cancer patients. Kidney function is closely related to patients' quality of life and tumor prognosis. Cisplatin is a highly effective anti-tumor drug. However, the use of cisplatin is limited by its nephrotoxicity. It has been reported that FGF21 has a renal-protective function, but the mechanisms by which it does so remain unclear. In this study, we show that the expression of FGF21 is significantly upregulated in both in vitro and in vivo cisplatin-induced AKI models. Administration of recombinant FGF21 to cisplatin-induced AKI mice resulted in significantly decreased blood urea nitrogen (BUN) and serum creatinine levels, as well as significantly reduced protein levels of kidney injury molecule-1 (TIM-1), C-caspase 3, and Bax. H&E-stained kidney sections from cisplatin-induced AKI mice treated with recombinant FGF21 showed a relatively normal renal tissue structure, a reduced number of necrotic sites and vacuolar changes, and decreased casts, suggesting alleviated renal tubular injury. Experiments with an AKI cell model (cisplatin-treated HK-2 cells) yielded similar results as the mouse model; recombinant FGF21 significantly downregulated protein expression levels of TIM-1, C-caspase 3, and Bax. Furthermore, administration of recombinant FGF21 to cisplatin-treated AKI models significantly increased SIRT1 expression, and the beneficial effects of FGF21 on kidney injury were reversed by SIRT1 knockdown. Collectively, our results suggest that SIRT1 mediates the protective effect of FGF21 on cisplatin-induced kidney injury.

Exercise Alleviates Obesity-Induced Metabolic Dysfunction via Enhancing FGF21 Sensitivity in Adipose Tissues.

Exercise promotes adipose remodeling and improves obesity-induced metabolic disorders through mechanisms that remain obscure. Here, we identify the FGF21 signaling in adipose tissues as an obligatory molecular transducer of exercise conferring its metabolic benefits in mice. Long-term high fat diet-fed obese mice exhibit compromised effects of exogenous FGF21 on alleviation of hyperglycemia, hyperinsulinemia, and hyperlipidemia, accompanied with markedly reduced expression of FGF receptor-1 (FGFR1) and ß-Klotho (KLB) in adipose tissues. These impairments in obese mice are reversed by treadmill exercise. Mice lacking adipose KLB are refractory to exercise-induced alleviation of insulin resistance, glucose dysregulation, and ectopic lipid accumulation due to diminished adiponectin production, excessive fatty acid release, and enhanced adipose inflammation. Mechanistically, exercise induces the adipose expression of FGFR1 and KLB via peroxisome proliferator-activated receptor-gamma-mediated transcriptional activation. Thus, exercise sensitizes FGF21 actions in adipose tissues, which in turn sends humoral signals to coordinate multi-organ crosstalk for maintaining metabolic homeostasis.

Pancreatic fibroblast growth factor 21 protects against type 2 diabetes in mice by promoting insulin expression and secretion in a PI3K/Akt signaling-dependent manner.

Fibroblast growth factor 21 (FGF21) is important in glucose, lipid homeostasis and insulin sensitivity. However, it remains unknown whether FGF21 is involved in insulin expression and secretion that are dysregulated in type 2 diabetes mellitus (T2DM). In this study, we found that FGF21 was down-regulated in pancreatic islets of db/db mice, a mouse model of T2DM, along with decreased insulin expression, suggesting the possible involvement of FGF21 in maintaining insulin homeostasis and islet ß-cell function. Importantly, FGF21 knockout exacerbated palmitate-induced islet ß-cell failure and suppression of glucose-stimulated insulin secretion (GSIS). Pancreatic FGF21 overexpression significantly increased insulin expression, enhanced GSIS, improved islet morphology and reduced ß-cell apoptosis in db/db mice. Mechanistically, FGF21 promoted expression of insulin gene transcription factors and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins, the major regulators of insulin secretion, as well as activating phosphatidylinositol 3-kinase (PI3K)/Akt signaling in islets of db/db mice. In addition, pharmaceutical inhibition of PI3K/Akt signaling effectively suppressed FGF21-induced expression of insulin gene transcription factors and SNARE proteins, suggesting an essential role of PI3K/Akt signaling in FGF21-induced insulin expression and secretion. Taken together, our results demonstrate a protective role of pancreatic FGF21 in T2DM mice through inducing PI3K/Akt signaling-dependent insulin expression and secretion.

FGF21 Prevents Angiotensin II-Induced Hypertension and Vascular Dysfunction by Activation of ACE2/Angiotensin-(1-7) Axis in Mice.

Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity. However, the role of FGF21 in hypertension remains elusive. Here we show that FGF21 deficiency significantly exacerbates angiotensin II-induced hypertension and vascular dysfunction, whereas such negative effects are reversed by replenishment of FGF21. Mechanistically, FGF21 acts on adipocytes and renal cells to promote induction of angiotensin-converting enzyme 2 (ACE2), which in turn converts angiotensin II to angiotensin-(1-7), then inhibits hypertension and reverses vascular damage. In addition, ACE2 deficiency strikingly abrogates these beneficial effects of FGF21 in mice, including alleviation of angiotensin II-associated hypertension and vascular damage. Otherwise, pharmaceutical inhibition of angiotensin-(1-7) attenuates the protective effect of FGF21 on angiotensin II-induced vascular dysfunction, but not on hypertension. Thus, FGF21 protects against angiotensin II-induced hypertension and vascular impairment by activation of the ACE2/angiotensin-(1-7) axis via fine-tuning the multi-organ crosstalk between liver, adipose tissue, kidney, and blood vessels.