Secreted Frizzled-related Protein 5 Research Articles

Secreted frizzled-related protein 5 protects against renal fibrosis by inhibiting Wnt/β-catenin pathway.

Renal fibrosis (RF) is an important pathogenesis for renal function deterioration in chronic kidney disease. Secreted frizzled-related protein 5 (SFRP5) is an anti-fibrotic adipokine but its direct role on RF remains unknown. It was aimed to study the protective effect of SFRP5 against RF and interference with Wnt/β-catenin signaling pathway for the first time. First, the therapeutic efficacy of SFRP5 was evaluated by adenovirus overexpression in rats with unilateral ureteral obstruction (UUO) in vivo. Thirty-six rats were randomly divided into the sham, UUO, and SFRP5 (UUO + Ad-SFRP5) groups. Half rats in each group were selected at random for euthanasia at 7 days and the others until 14 days. Then, the transforming growth factor (TGF)-β1-induced epithelial-mesenchymal transition (EMT) was established in HK-2 cells in vitro. The cells were divided into four groups: the control group, the TGF-β1 group, the TGF-β1 + SFRP5 group, and the TGF-β1 + SFRP5 + anti-SFRP5 group. The makers of EMT and Wnt/β-catenin pathway proteins were investigated. In the UUO model, expression of SFRP5 showed compensatory upregulation, and adenoviral-mediated SFRP5 over-expression remarkably attenuated RF, as demonstrated by maintenance of E-cadherin and suppression of α-smooth muscle actin (SMA). In vitro, SFRP5 was shown to inhibit TGF-β1-mediated positive regulation of α-SMA, fibronectin, collagen I but negative regulation of E-cadherin. Furthermore, SFRP5 abrogated activation of Wnt/β-catenin, which was the essential pathway in EMT and RF pathogenesis. The changes after a neutralizing antibody to SFRP5 confirmed the specificity of SFRP5 for inhibition. These findings suggest that SFRP5 can directly ameliorate EMT and protect against RF by inhibiting Wnt/β-catenin pathway.

Associations of levels of high-molecular-weight adiponectin, secreted frizzled-related protein 5 and vascular endothelial growth factor-165 with diabetic retinopathy

Abstract Background: The pathogenesis of diabetic retinopathy (DR) remains unclear. The aim of the study was to explore the associations of DR with the levels of high-molecular-weight adiponectin (HMW-ADP), secreted frizzled-related protein 5 (SFRP-5) as well as vascular endothelial growth factor-165 (VEGF165). Methods: Based on the diagnostic criteria for DR, non-DR (NDR), proliferative DR (PDR) plus non-proliferative DR (NPDR) groups were set up for type 2 diabetes mellitus (T2DM) patients (n=180) treated from January 2020 to March 2021. The control group consisted of another 60 healthy subjects undergoing physical examinations. Their clinical data were compared. Receiver operating characteristic curves were plotted to assess the predictive values of HMW-ADP, VEGF165 and SFRP-5 for DR. The predictive efficiency of the established nomogram model was assessed. Results: The differences in age, fasting plasma glucose (FPG), T2DM duration, triglyceride (TG), hypertension history, high-density lipoprotein cholesterol (HDL-C), glycosylated haemoglobin (HbA1c), serum creatinine (Scr), homeostasis model assessment of insulin resistance (HOMA-IR), urine acid (UA), SFRP-5 HMW-ADP, and VEGF165 were significant between control and DR groups (P<0.05). HMW-ADP, VEGF165 and SFRP-5 had predictive values for DR (AUC>0.7), and the predictive efficiency of their combination was highest. The duration of T2DM, Scr, UA and VEGF165 were independent risk factors for DR, while HMW-ADP and SFRP-5 were protective factors (P<0.05). Preferable discrimination and accuracy together with clinical applicability were obtained for the nomogram prediction model. Conclusions: The three indicators as a whole have a high predictive value for DR, as potential indicators for the clinical screening of high-risk groups.

Secreted frizzled-related protein 5: A promising therapeutic target for metabolic diseases via regulation of Wnt signaling

Metabolic diseases pose a significant global health challenge, characterized by an imbalance in metabolism and resulting in various complications. Secreted frizzled-related protein 5 (SFRP5), an adipokine known for its anti-inflammatory properties, has gained attention as a promising therapeutic target for metabolic diseases. SFRP5 acts as a key regulator in the Wnt signaling pathway, exerting its influence on critical cellular functions including proliferation, differentiation, and migration. Its significance extends to the realm of adipose tissue biology, where it plays a central role in regulating inflammation, insulin resistance, adipogenesis, lipid metabolism, glucose homeostasis, and energy balance. By inhibiting Wnt signaling, SFRP5 facilitates adipocyte growth, promotes lipid accumulation, and contributes to a decrease in oxidative metabolism. Lifestyle interventions and pharmacological treatments have shown promise in increasing SFRP5 levels and protecting against metabolic abnormalities. SFRP5 is a pivotal player in metabolic diseases and presents itself as a promising therapeutic target. An overview of SFRP5 and its involvement in metabolic disorders and metabolism is provided in this comprehensive review. By elucidating these aspects, valuable insights can be gained to foster the development of effective strategies in combating metabolic diseases.

Association of Circulating Plasma Secreted Frizzled-Related Protein 5 (Sfrp5) Levels with Cardiac Function.

Secreted frizzled-related protein 5 (SFRP5) is a novel anti-inflammatory adipokine that may play a role in cardiovascular development and disease. However, there is yet to be a comprehensive investigation into whether circulating SFRP5 can be a biomarker for cardiac function. Plasma SFRP5 levels were measured via ELISA in 262 patients admitted to a cardiology unit. Plasma SFRP5 levels were significantly lower in patients with a history of heart failure (HF), coronary artery disease (CAD), and atrial fibrillation (AF; p = 0.001). In univariate analyses, SFRP5 levels were also significantly positively correlated with left ventricular ejection fraction (LVEF) (r = 0.52, p < 0.001) and negatively correlated with E/E' (r = -0.30, p < 0.001). Patients with HF, CAD, low LVEF, low triglycerides, high CRP, and high eGFR were associated with lower SFRP5 levels independent of age, BMI, or diabetes after multivariate analysis (overall model r = 0.729, SE = 0.638). Our results show that low plasma SFRP5 levels are independently associated with the presence of HF, CAD, and, importantly, impaired LV function. These results suggest a potential role of SFRP5 as a biomarker, as well as a mediator of cardiac dysfunction independent of obesity and metabolic regulation.

SFRP5 as a new cardiovascular biological marker: a literature review

Research into new biological markers may help early diagnosis and effective therapy for cardiology patients. The use of biomarkers to evaluate patients has made a major impact in oncology, but is still in its infancy in the cardiology field. Studies on secreted frizzled-related protein 5 (SFRP5) have revealed its potential use as a marker of cardiovascular pathology. Preclinical studies have highlighted the important role this protein plays in many biological processes. It reduces the proliferation and migration of cardiac fibroblasts and suppresses the Wnt5A/JNK signaling pathway thus reducing the severity of oxidative stress and inflammation. It normalizes nitric oxide production and has several other effects. However, recent clinical studies of SFRP5 have produced conflicting data. Nevertheless, this protein shows promise as a marker for several metabolic and cardiovascular diseases. Preliminary data also suggest SFRP5 may be a therapeutic target. Further study of SFRP5 and its role in cardiovascular pathology is necessary, and will create new diagnostic and prognostic possibilities for this biological marker.

Leptin/SFRP5 ratio as a potential predictor of postpartum weight retention. A prospective pilot study.

Excessive gestational weight gain (EGWG) and failure to lose weight within 6 months from delivery are important and identifiable predictors of the long-term obesity. The aim of the study was to verify clinical usefulness of several substances that had been proved to play a significant role in metabolism and body mass regulation, i.e., leptin, ghrelin, fatty acid binding protein 4 (FABP4), secreted frizzled-related protein 5 (SFRP5), and vaspin, in relation to certain laboratory results, body composition and hydration status of females in the early postpartum period. The main goal was to determine a potential marker, which assessed as early as 48 hours after delivery, could predict serious difficulties in achieving pre pregnancy body mass of women with EGWG six months afterwards. The same inclusion criteria applied to the study group (women with EGWG) as well as the control group (women with appropriate body mass gain in pregnancy). These included normal pre-pregnancy BMI, absence of any diseases prior, during pregnancy and after delivery, 6-month long breastfeeding. Postpartum weight retention (PPWR) depended positively on gestational weight gain as well as the leptin/SFRP5 ratio assessed 48 hours after delivery. Both obstetricians and midwives should pay special attention to proper nutrition of pregnant women. The assessment of biophysical and biochemical parameters in the early postpartum period, when the mothers are usually hospitalized, seems to allow to predict the risk of greater body weight retention. Future research will help to determine to what extent the circulating concentrations of leptin and SFRP5 in the early puerperium are important for prediction of maternal PPWR and obesity.

Secreted Frizzled Related Protein 5 (SFRP5) Serum Levels Are Decreased in Critical Illness and Sepsis and Are Associated with Short-Term Mortality

Sepsis is a major health burden with insufficiently understood mechanisms of inflammation and immune paralysis, leading to a life-threatening critical illness. The secreted frizzled related protein 5 (SFRP5) acts as an anti-inflammatory adipokine by antagonizing the Wnt5a pathway. The aim of this study was to elucidate the role of SFRP5 in critical illness and sepsis and to determine its value as a prognostic biomarker for mortality. We analyzed SFRP5 serum concentrations of 223 critically ill patients at admission to a medical intensive care unit (ICU) and compared those to 24 healthy individuals. SFRP5 serum concentrations were significantly decreased in critical illness as compared to healthy controls (24.66 vs. 100 ng/mL, p = 0.029). Even lower serum concentrations were found in septic as compared to nonseptic critically ill patients (19.21 vs. 32.83 ng/mL, p = 0.031). SFRP5 concentrations correlated with liver disease, age, anti-inflammation, and metabolic parameters. Furthermore, patients with sepsis recovered levels of SFRP5 in the first week of ICU treatment. SFRP5 levels at admission predicted short-term mortality in critically ill but not in septic patients. This study points to the role of the anti-inflammatory mediator SFRP5 not only in sepsis but also in nonseptic critically ill patients and associates high levels of SFRP5 to worse outcomes, predominantly in nonseptic critically ill patients.

Frizzled receptors and SFRP5 in lipid metabolism: Current findings and potential applications.

Lipid metabolism plays a very important role as the central metabolic process of the body. Lipid metabolism interruptions may cause many chronic diseases, for example, non-alcoholic fatty liver disease (NAFLD), diabetes, and obesity. Secreted Frizzled Related Protein 5 (SFRP5) and Frizzled receptors (FZD) are two newly discovered adipokines that are involved in lipid metabolism as well as lipogenesis. Both of these adipokines affect lipid metabolism and adipogenesis through three WNT signaling pathways (WNTSP): WNT/β-catenin, WNT/Ca2+, and WNT/JNK. FZD consists of 10 species, which have a cysteine-rich domain (CRD) to bind to the WNT protein for signal transduction. Depending on the type of ligand or co-receptor, they can stimulate or inhibit adipogenesis. In lipid metabolism, they play a role in recognizing fatty acids. In obesity, gene expression of the WNT/FZD receptors is significantly increased. In contrast, SFPR5 serves as an antagonist that can compete with FZD for inhibition of WNTSP. It is believed to have anti-inflammatory potential in obesity and diseases related to abnormal lipid metabolism. In these cases, the expression of SFRP5 is found to be very low leading to the promoted production of proinflammatory cytokines (PICS). Some methods that include using recombinant SFRP5 to improve non-alcoholic steatohepatitis (NASH), using secreted Ly-6/uPAR-related protein 1 (Slurp1) to regulate fat accumulation in the liver through SFRP5, and dietary and lifestyle interventions to improve overweight/obesity have been studied. However, understandings of the molecular mechanisms of these two adipokines and their interactions are very limited. Therefore, more in-depth studies are needed in the future.

Heart failure is associated with low circulating levels of secreted frizzled receptor protein 5 (Sfrp5)

Abstract Background/Introduction Obesity and metabolic dysregulation are closely associated with the pathophysiology of multiple cardiovascular diseases (CVD). To date, the pathophysiological mechanism(s) of obesity and its link with cardiovascular systems remain largely unknown. Adipose tissue inflammation as a result of excessive fat expansion in obesity, leading to increased systemic production of growth factors and recruitment of inflammatory cells have been postulated to be a major factor. Secreted frizzled-related protein 5 (SFRP5) is an anti-inflammatory adipokine that is linked with obesity and metabolic regulation and has been indicated to affect cardiovascular functions. Currently, the role of circulating SFRP5 levels as a biomarker for cardiovascular diseases are poorly understood, with studies yielding discordant results. Purpose This study aims to evaluate the relationship between circulating SFRP5 and cardiovascular functions in a cohort of patients with established CVD. Methods Patients (n=262, 148 male (56.5%), age (68±11 yrs)) presenting to the cardiology unit for cardiovascular investigations were recruited into the study. Plasma SFRP5 levels were measured via enzyme-linked immunosorbent assay (ELISA). Associations between plasma SFRP5 levels, cardiovascular functions, and patients' co-morbidities were analysed using univariate and multivariate analyses. Results Plasma SFRP5 levels were significantly lower in patients presenting with: heart failure (HF) vs non-HF (median; (10.7 vs 31.0; p&amp;lt;0.001); coronary artery disease (CAD) vs non-CAD; (11.0 vs 33.8; p&amp;lt;0.001); and atrial fibrillation (AF) vs non-AF; (11.2 vs 23.2; p=0.001). On univariate analyses, SFRP5 levels also significantly positively correlated with left ventricular ejection fraction (LVEF) (r=0.52, p&amp;lt;0.001), estimated glomerular filtration rate (eGFR) (r=0.16, p=0.02), total cholesterol levels and triglycerides (r=0.29, p&amp;lt;0.001; r=0.17, p&amp;lt;0.01 respectively). Low SFRP5 levels were correlated with high C-reactive protein (CRP) and E/E' (r=−0.29, p&amp;lt;0.001, r=−0.30, p&amp;lt;0.001, respectively). Patients with HF, CAD, statin use, low LVEF, low triglycerides, high CRP and high eGFR were associated with lower SFRP5 levels independent of age, BMI or diabetes on multivariate analysis (overall model r=0.729, SE=0.638). Conclusion Our results show that low plasma SFRP5 levels are independently associated with HF, CAD, and impaired systolic and diastolic functions. These results suggest that SFRP5 may regulate cardiovascular functions independent of obesity and metabolic regulations. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Heart Foundation of Australia Future Leader FellowshipsNSW Ministry of Health EMC FellowshipHeart Foundation of Australia Future Leader Fellowship

Increased Secreted Frizzled-Related Protein 5 mRNA Expression in the Adipose Tissue of Women with Nonalcoholic Fatty Liver Disease Associated with Obesity

Secreted frizzled-related protein 5 (SFRP5) is an anti-inflammatory adipocytokine secreted by adipocytes that seems to be linked with nonalcoholic fatty liver disease (NAFLD). We aimed to evaluate the role of the SFRP5-wingless-MMTV integration site family member 5a (WNT5A) pathway, closely related to adipogenesis, in subcutaneous (SAT) and visceral adipose tissues (VAT) and its relationship with obesity-related NAFLD. Our cohort was composed of 60 women with morbid obesity (MO), who underwent hypocaloric diet, subclassified according to their hepatic histopathology and 15 women with normal weight. We observed increased SFRP5 mRNA expression in VAT and lower WNT5A expression in SAT in MO compared to normal weight. We found elevated SFRP5 expression in nonalcoholic steatohepatitis (NASH) in SAT and in mild simple steatosis (SS) and NASH in VAT. We observed higher WNT5A expression in SS compared to normal liver in SAT, and a peak of WNT5A expression in mild SS. To conclude, we reported increased SFRP5 mRNA expression in SAT and VAT of NAFLD-related to obesity subjects, suggesting an implication of the SFRP5-WNT5A pathway in NAFLD pathogenesis, probably due to the adipose tissue-liver axis. Since the mechanisms by which this potential interaction takes place remain elusive, more research in this field is needed.

Effects of Dapagliflozin in Combination with Metoprolol Sustained-Release Tablets on Prognosis and Cardiac Function in Patients with Acute Myocardial Infarction after PCI.

Objective To find the effects of dapagliflozin in combination with metoprolol sustained-release tablets on cardiac function and prognosis in acute myocardial infarction patients after PCI. Methods A total of 84 patients with myocardial infarction who experienced PCI from February 2020 to February 2022 were included and allocated into 3 groups: groups A, B, and C (n = 28/per group). Group A was given dapagliflozin combined with metoprolol sustained-release tablets, group B was given dapagliflozin, and group C was given the placebo. Left ventricular end diastolic diameter (EDD), left ventricular ejection fraction (LVEF), and end systolic diameter (ESD) were measured before and after treatment in all groups; myocardial infarction areas were matched among all three groups at 3 months posttreatment. The serum concentrations of interleukin-6 (IL-6), hypersensitive C-reactive protein (hs-CRP), superoxide dismutase (SOD), and malondialdehyde (MDA) were detected in all three groups before and after treatment. The levels of N-terminal probrain natriuretic peptide (NT-pro BNP), lipoprotein (a) (Lp(a)), ischemia-modified albumin (IMA), and secreted frizzled-related protein 5 (SFRP5) were also detected in the serum of all groups. Adverse reactions and cardiovascular adverse events were matched between all groups. Results The levels of LVEF in groups A and B were increased after treatment, while the levels of EDD and ESD were decreased. The improvement degree of LVEF and EDD levels in groups A and B was found greater compared to group C (P < 0.05). No significant difference was found in myocardial infarction area among the three groups at 3 months postoperation (P > 0.05). Serum concentrations of MDA, hs-CRP, IL-6, IMA, NT-proBNP, and Lp(a) were found to decrease in all three groups after treatment, while the levels of SOD and SFRP5 were increased. The improvement degree of serum hs-CRP, IL-6, SOD, MDA, IMA, NT-proBNP, Lp(a), and SFRP5 levels was greater in both groups A and B compared to group C. The improvement degree of serum hS-CRP, SOD, MDA, IMA, Nt-probNP, Lp(a), and SFRP5 levels was significantly greater in group A compared to group B (P < 0.05). No adverse effect was observed in all three groups (P > 0.05). Total occurrence of cardiovascular adverse effects such as stent thrombosis, heart failure, ventricular fibrillation, and death was 10.71% in group A, 25.00% in group B, and 53.75% in group C. There was statistical significance in the onset of cardiovascular adverse effects 3 months postoperation among all three groups (P < 0.05). Conclusion Dapagliflozin with metoprolol sustained-release tablets can be effective in improving the heart function, inflammatory response, oxidative stress response, and prognosis in patients after PCI.

Effect of Secreted Frizzled-Related Protein 5 in Mice with Heart Failure.

Although some progress has been made in its treatment, heart failure is still one of the most important health problems that endanger public health. This study aims to explore the myocardial protective effect of secreted frizzled-related protein 5 (SFRP5) on mice with heart failure. The mouse model of heart failure was established by using the isoproterenol (ISO) hydrochloride gradient modeling method. The treatment group was injected with 0.02 mg/kg/24 h SFRP5 recombinant protein intraperitoneally 30 minutes after the injection of isoproterenol, and the ISO + phosphate-buffered saline (PBS) group was injected with the same amount of PBS. After intraperitoneal injection of SFRP5 recombinant protein in mice with heart failure, the inflammatory response was reduced, and the left ventricular systolic and diastolic function of heart failure mice and the pathological structure of the myocardial tissue were improved. Compared with the ISO group, the expression level of SFRP5 protein in the ISO + SFRP5 group was increased significantly, the expression levels of Wnt5a and JNK protein were decreased markedly, and the enzyme activities of SOD and GSH-Px in the serum were observably increased, but they were lower than those parameters in the normal group. The SFRP5 recombinant protein has a protective effect on isoproterenol-induced heart failure in mice. The mechanism of action may be related to inhibiting the Wnt5A/JNK signaling pathway and reducing oxidative stress and inflammation. SFRP5 may be one of the therapeutic targets of heart failure.

Secreted frizzled-related protein 5 promotes angiogenesis of human umbilical vein endothelial cells and alleviates myocardial injury in diabetic mice with myocardial infarction by inhibiting Wnt5a/JNK signaling

ABSTRACT The purpose of this study is to investigate whether secreted frizzled-related protein 5 (SFRP5) affects the proliferation, migration and angiogenesis of human umbilical vein endothelial cells (HUVECs) induced by high glucose (HG). HUVECs were treated with different concentrations of glucose. MTT, wound healing, angiogenesis, and ELISA assays were used to detect cell cytotoxicity, migration, tube formation, and VEGF165 and VEGF165b levels, respectively. The mice model of type 2 diabetes mellitus (T2DM) complicated with myocardial infarction (MI) was established. SFRP5 was injected intrabitoneally for 2 weeks. cardiac output (CO), left ventricular ejection fraction (LVEF) and left ventricular shortening fraction (LVSF) were detected by echocardiography. Western blot was used to detect the protein levels of SFRP5, Wnt5a, JNK1/2/3, p-JNK1/2/3, TGF-β1, Caspase3, Bax, and Bcl-2. The expression of SFRP5 was declined in HG-induced HUVECs and T2DM-MI. Intervention of SFRP5 promoted the migration of HUVECs and angiogenesis, as evidenced by a lower expression of Bax and caspase3, but a higher expression of Bcl-2. Meanwhile, SFRP5 inhibition repress Wnt5a and p-JNK expression. Howerver, The JNK inhibitor (SP600125) enhanced the down-regulation of Wnt5a/JNK pathway proteins by SFRP5. SFRP5 intervention increased the levels of CO, LVSF, and LVEF in T2DM-MI mice. SFRP5 inhibited myocardial pathological injury and fibrosis in T2DM-MI mice and SFRP5 could down-regulate Wnt5a and p-JNK1/2/3 activation. SFRP5 promotes the proliferation, migration and angiogenesis of HUVECs induced by HG, and inhibits cardiac dysfunction, pathological damage, fibrosis, and myocardial angiogenesis in diabetic myocardial ischemia mice, which is achieved by inhibiting Wnt5a/JNK signaling.

Systemic and ovarian inflammation in women with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common endocrine/reproductive/metabolic disorder. The etiology of PCOS is complex and has been linked to low-grade chronic inflammation. Local inflammation of the ovary affects ovulation and induces or aggravates systemic inflammation. PCOS patients demonstrated significantly higher concentrations of circulating inflammatory cells, such as lymphocytes, neutrophils, eosinophilic granulocytes, monocytes and Th17 cells than women without PCOS, while the percentage of Treg cells was lower. Inflammatory factors, such as serum CRP, hs-CRP, IL-1Ra, IL-6, IL-17A, IL-17F, IL-18, IL-23, TNF-α, α-1 acid glycoprotein,monocyte chemoattractant protein-1 (MCP-1) and adipokines and their paralogs, including chemerin, C1q and TNF-related 6 (C1QTNF6), were also found to be significantly increased in the peripheral blood of PCOS patients. Levels of anti-inflammatory cytokines, such as IL-10, IL-17E, IL-27, IL-35 and IL-37, TGF-β, omentin-1, Secreted frizzled-related protein5 (SFRP5) were significantly lower. An analogous situation occurs locally in the ovary. Some vital inflammatory cells and cytokines may initially be released from the ovary and then enter the circulation. The systemic inflammation underlying PCOS is thought to interact with obesity, insulin resistance (IR) and hyperandrogenism. Traditional Chinese medicine, multitargeted treatment, anti-inflammatory and antioxidant medicine, and lifestyle modification can benefit PCOS women by alleviating inflammatory responses.

The Role of Anti-Inflammatory Adipokines in Cardiometabolic Disorders: Moving beyond Adiponectin.

The global burden of obesity has multiplied owing to its rapidly growing prevalence and obesity-related morbidity and mortality. In addition to the classic role of depositing extra energy, adipose tissue actively interferes with the metabolic balance by means of secreting bioactive compounds called adipokines. While most adipokines give rise to inflammatory conditions, the others with anti-inflammatory properties have been the novel focus of attention for the amelioration of cardiometabolic complications. This review compiles the current evidence on the roles of anti-inflammatory adipokines, namely, adiponectin, vaspin, the C1q/TNF-related protein (CTRP) family, secreted frizzled-related protein 5 (SFRP5), and omentin-1 on cardiometabolic health. Further investigations on the mechanism of action and prospective human trials may pave the way to their clinical application as innovative biomarkers and therapeutic targets for cardiovascular and metabolic disorders.

PPARγ attenuates hepatic inflammation and oxidative stress of non‑alcoholic steatohepatitis via modulating the miR‑21‑5p/SFRP5 pathway.

Inflammation and oxidative stress are key steps in the progression of non-alcoholic steatohepatitis (NASH). Intervention in these two processes will therefore benefit NASH treatment. Peroxisome proliferator-activated receptor γ (PPARγ), as a multiple functional transcription factor, has been reported to be involved in the prevention of NASH progression. However, the mechanism by which PPARγ prevents NASH remains to be elucidated. The present study demonstrated that the level of PPARγ was inversely correlated with that of microRNA (miRNA/miRs)-21-5p in both mice and humans with NASH. Activation of PPARγ inhibited lipid droplet accumulation, hepatic inflammation and oxidative stress by downregulating miR-21-5p in an in vitro model. Luciferase reporter and chromatin immunoprecipitation assays demonstrated that PPARγ suppressed transcriptional activity of miR-21-5p and bound to miR-21-5p promoter region. Furthermore, PPARγ downregulated miR-21-5p while miR-21-5p upregulated secreted frizzled-related protein 5 (SFRP5) by targeting the 3′-UTR of its mRNA. In vivo experiments revealed that PPARγ repressed inflammation and oxidative stress and miR-21-5p expression while increased SFRP5 level in a NASH mouse model. In summary, PPARγ attenuates inflammation and oxidative stress in NASH by modulating the miR-21-5p/SFRP5 pathway, thus holding promise of a new target for NASH treatment.

Deregulation of Secreted Frizzled-Related Protein 5 in Nonalcoholic Fatty Liver Disease Associated with Obesity

Secreted frizzled-related protein 5 (SFRP5), an antagonist of the noncanonical WNT pathway, has a controversial role in liver disease. The aim of this study was to analyze the role of SFRP5 and the noncanonical WNT pathway in nonalcoholic fatty liver disease (NAFLD). Plasma SFRP5 levels were determined by ELISA in women with normal weight (NW; n = 20) and morbid obesity (MO; n = 69). Women with MO were subclassified according to hepatic histology into normal liver (NL; n = 28), NAFLD (n = 41) (simple steatosis (SS; n = 24), and nonalcoholic steatohepatitis (NASH; n = 17)). We used RT-qPCR to evaluate the hepatic mRNA expression of SFRP5, WNT5A, and JNK in women with MO. SFRP5 levels were lower in NW than in MO patients who underwent a very low-calorie diet before surgery. Hepatic SFRP5 mRNA expression was higher in SS than in NL or NASH; additionally, patients with hepatic inflammation or ballooning presented lower SFRP5 abundance. WNT5A and JNK expression was enhanced in NAFLD compared with NL. In conclusion, circulating SFRP5 levels depend on the diet, and hepatic SFRP5 seems to have a protective role in the first steps of NAFLD; however, SFRP5 could be deregulated in an advanced stage while WNT5A and JNK are activated, promoting liver damage.

Secreted Frizzled-Related Protein 5 is Associated with Glucose and Lipid Metabolism Related Metabolic Syndrome Components Among Adolescents in Northeastern China.

PurposeSecreted frizzled-related protein 5 (SFRP5) is a novel anti-inflammatory adipokine that has been associated with various metabolic diseases. However, such relationship among adolescents remains unclear. The purpose of this study was to clarify the relationship between SFRP5 and the components of metabolic syndrome in Chinese adolescents.Patients and MethodsIn this cross-sectional study, we included a total of 684 adolescents aged 11–16 years old from Liaoyang city, Liaoning province, China. The ELISA kits were implemented to measure the plasma SFRP5 and high-sensitivity C-reactive protein. Serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C), serum uric acid (UA), alanine aminotransferase (ALT), aspartate aminotransferase (AST), fasting plasma glucose (FPG), and fasting serum insulin (FINS) were also measured.ResultsThe multivariate logistic regression analysis showed that low SFRP5 level were an independent risk factor of high FPG [odds ratio (OR)=5.31, 95% confidence interval (CI): 1.85–15.22, P<0.01] and high TC (OR=1.73, 95% CI: 1.01-2.96, P<0.05) when adjusting for age, sex, family history of diabetes, body mass index, and high-sensitivity C-reactive protein.ConclusionThe lower level of SFRP5 is strongly related to lipid and glucose metabolism among adolescents in Northeast China. The risk of high fasting plasma glucose and high total cholesterol increases significantly as the plasma SFRP5 level decreases.

The effects of S-nitrosylation-induced PPARγ/SFRP5 pathway inhibition on the conversion of non-alcoholic fatty liver to non-alcoholic steatohepatitis.

BackgroundPeroxisome proliferators-activated receptors γ (PPARγ) and secreted frizzled related protein 5 (SFRP5) are abnormally expressed in liver cells. But their role in the transformation of non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH) remains to be studied. We aimed to explore the role of S-nitrosylation (SNO) in the conversion of NAFL to NASH via the peroxisome PPARγ/SFRP5 pathway.MethodsA normal diet and methionine-choline deficient diet were used to construct the NAFL and NASH mouse models, respectively. The differences between the SNO of PPARγ in both models were measured by irreversible biotinylation. Quantitative reverse transcription PCR (qRT-PCR) and Western blotting were used to detect the effect of SNO on the expression of PPARγ messageRNA (mRNA) and protein in L02 hepatocytes. Nubiscan software, luciferase reporter gene, and chromatin immunoprecipitation assay (CHIP) were used to verify the targeting relationship between PPAR and SFRP5. The expression of tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), and interleukin-6 (IL-6), which are indicators for the activation of Kupffer cells, were determined by enzyme linked immunosorbent assay (ELISA) after co-cultivation of L02 hepatocytes and Kupffer macrophages, as well as the exogenous regulation of SNO, PPARγ, and SFRP5 in hepatic L02 cells.ResultsThe NAFL and NASH mouse models were successfully constructed, and the level of PPARγ SNO in the NAFL model was significantly lower than the NASH model (P<0.05). The level of PPARγ was significantly downregulated after increasing the SNO of L02 cells, respectively (P<0.05). Nubiscan software and CHIP confirmed that PPARγ could bind to the promoter region of SFRP5 (P<0.05). Overexpression of PPARγ and SFRP5 could significantly downregulate the expression of TNFα, IL-1β, and IL-6 (P<0.05) correspondingly, while increasing the SNO level of L02 cells could restore the expression levels of TNFα, IL-1β, and IL-6.ConclusionsSNO promoted the activation of macrophage Kupffer cells by inhibiting the PPARγ/SFRP5 pathway in L02 hepatocytes, thereby promoting the conversion of NAFL into NASH.

MiR-124-3p Down-Regulation Influences Pancreatic-β-Cell Function by Targeting Secreted Frizzled-Related Protein 5 (SFRP5) in Diabetes Mellitus

Diabetes mellitus (DM) is a complex metabolic disease characterized by hyperglycemia, insulin resistance and pancreatic β-cell dysfunction. There are evidences showed that microRNAs (miRNAs) play important roles in DM. The purpose of our study was to determine the role of miR-124-3p in DM. Quantitative reverse transcription PCR (qRT-PCR) was applied to measure the level of miR- 124-3p in peripheral blood from healthy control patients and DM patients. Then we explored the effects of miR-124-3p inhibitor on the secretion of insulin of pancreatic β-cells. Moreover, we determined the effects of miR-124-3p inhibitor on the apoptosis and viability of pancreatic β-cells through flow cytometry and MTT assay. And we also used western blotting to detect the protein expression of cleaved-caspase3/pro-caspase3, and the activity of caspase3 was detected. In addition, we confirmed the direct target of miR-124-3p using Dual luciferase reporter assay. Our data showed that in the blood of DM patients, SFRP5 was significantly reduced, while miR-124-3p was increased significantly. Furthermore, we found that down-regulation of miR-124-3p increased total insulin content in INS-1 cells, enhanced insulin secretion in INS-1 cells. Furthermore, we revealed that miR-124-3p inhibitor enhanced INS-1 cell viability, decreased apoptosis of INS-1 cells, increased pro-caspase3 expression, decreased cleaved-caspase3 expression and caspase3 activity. In addition, we proved SFRP5 was a direct target of miR-124-3p in pancreatic β-cells. Moreover, SFRP5-siRNA reversed all the effects of miR-124-3p knockdown on pancreatic β-cells.