Secreted Frizzled-Related Protein 5 Mediates Wnt5a Expression in Microcystin-Leucine-Arginine-Induced Liver Lipid Metabolism Disorder in Mice

Objective Microcystin-leucine-arginine(MC-LR)exposure induces lipid metabolism disorders in the liver.Secreted frizzled-related protein 5(SFRP5)is a natural antagonist of winglesstype MMTV integration site family,member 5A(Wnt5a)and an anti-inflammatory adipocytokine.In this study,we aimed to investigate whether MC-LR can induce lipid metabolism disorders in hepatocytes and whether SFRP5,which has anti-inflammatory effects,can alleviate the effects of hepatic lipid metabolism by inhibiting the Wnt5a/Jun N-terminal kinase(JNK)pathway.Methods We exposed mice to MC-LR in vivo to induce liver lipid metabolism disorders.Subsequently,mouse hepatocytes that overexpressed SFRP5 or did not express SFRP5 were exposed to MC-LR,and the effects of SFRP5 overexpression on inflammation and Wnt5a/JNK activation by MC-LR were observed.Results MC-LR exposure induced liver lipid metabolism disorders in mice and significantly decreased SFRP5 mRNA and protein levels in a concentration-dependent manner.SFRP5 overexpression in AML12cells suppressed MC-LR-induced inflammation.Overexpression of SFRP5 also inhibited Wnt5a and phosphorylation of JNK.Conclusion MC-LR can induce lipid metabolism disorders in mice,and SFRP5 can attenuate lipid metabolism disorders in the mouse liver by inhibiting Wnt5a/JNK signaling.

Secreted Frizzled-Related Protein 5 (SFRP5) in Patients with Obstructive Sleep Apnea

Objective Obstructive sleep apnea (OSA) is closely related to obesity, insulin resistance and inflammation. Secreted frizzled-related protein 5 (SFRP5) is a recently discovered adipokine. It is involved in insulin resistance and inflammation in obesity. This study aimed at evaluating the association between SFRP5and sleeping characteristics as well as biochemical parameters of OSA patients.Methods This was a prospective case control study. Nondiabetic OSA patients and controls were consecutively recruited and divided into three groups: OSA group, apnea–hypopnea Index (AHI)≥5/h; healthy controls with normal body mass index (BMI); obese controls without OSA, and BMI > 24.0 kg/m2. All participants underwent polysomnography (PSG). Plasma SFRP5 was examined using enzyme-linked immunosorbent assay (ELISA). Blood biochemical examinations, including fasting blood glucose (FBG), lipid profile, hypersensitive Creactive protein (hsCRP), were performed early in the morning after PSG. Patients with severe OSA were treated with nasal continuous positive airway pressure (nCPAP), and plasma SFRP5 was repeatedly measured for comparison.Results Sixty-eight subjects were enrolled in the study, including 38 patients of OSA, whose medium AHI was 58.70 /h (36.63, 71.15), 20 obese controls, and 10 healthy controls. The plasma SFRP5 level of OSA patients was not significantly different from that of healthy controls or obese controls. In OSA patients, SFRP5 level correlated positively with triglyceride level (r=0.447, P=0.005) and negatively with LDL-cholesterol level and HDLcholesterol level (r=?0.472 and P=0.003; r=?0.478 and P=0.002; respectively). SFRP5 level was not found correlating with FBG, AHI, or any of nocturnal hypoxia parameters. After overnight nCPAP treatment, plasma SFRP5 levels of OSA patients did not change significantly (t=1.557, P = 0.148) compared to that of pretreatment.Conclusions In nondiabetic OSA patients, plasma SFRP5 is associated with the lipid profile. However,no correlation was observed between SFRP5 and FBG or sleep parameters. The SFRP5 level of OSA patients did not differ from that of non-OSA individuals in our study.

Combination analysis of hypermethylated SFRP1 and SFRP2 gene in fecal as a novel epigenetic biomarker panel for colorectal cancer screening

Objective：To investigate the feasibility of the combination of detecting hypermethylated secreted frizzled-related protein 1 （SFRP1） and secreted frizzled-related protein 2（SFRP2） in feces as a panel of biomarkers for colorectal cancer（CRC） screening. Methods： Methylation-specific PCR（MSP） was performed to analyze methylation status of SFRP1 and SFRP2 in a blinded fashion in tumor tissues and in matched stool samples from 39 patients with primary CRC, 34 patients with adenomas, 17 patients with hyperplastic polyps and 20 endoscopically normal subjects as normal controls. Simultaneously we analyzed the correlation of hypermethylated SFRP1 and SFRP2 with the clinicopathological features of CRC. Results：Hypermethylated SFRP1 was detected in 92.3%, 76.5%, 47.1% of tissue samples and in 89.7%, 64.7%, 35.3% of matched fecal samples from CRC, adenoma and hyperplastic polyp, respectively. Hypermethylated SFRP2 was detected in 87.2%, 67.6%, 35.3% of tissue samples and in 82.1%, 55.9%, 29.4% of matched fecal samples from CRC, adenoma and hyperplastic polyp, respectively. Of these two genes, at least one hypermethylated was 94.9%, 82.4%, 52.9% in tissue samples and 92.3%,73.5%, 47.1% in matched fecal samples from CRC, adenoma and hyperplastic polyp, respectively. In contrast, no hypermethylated SFRP1 and SFRP2 were detected in mucosa tissues of normal controls, only 2 cases of fecal samples was detected with hypermethylated SFRP1 and another 1 case was detected with hypermethylated SFRP2. Moreover, no significant associations were observed between hypermethylated SFRP1,SFRP2 and clinicopathological features of CRC. Conclusion： Hypermethylation of SFRP1 and SFRP2 in feces are novel epigenetic biomarkers of CRC and carded high potential for the remote detection of CRC as non-invasive screening method, and combined analysis of hypermethylated SFRP1 and SFRP2 in fecal could further increase the detection rate of CRC and premalignant lesions.

分泌性卷曲相关蛋白5表达上调对小鼠肝脏糖代谢的影响

分泌性卷曲相关蛋白5(secreted frizzled-related protein 5,SFRP5)是一种抗炎脂肪因子,它与糖尿病密切相关,具有抗糖尿病作用。将8周龄的C57BL/6J小鼠随机分为4组:普食-空载病毒组(SD+Ad-GFP组,n=10)、普食-SFRP5过表达病毒组(SD+Ad-SFRP5组,n=10)、高脂-空载病毒组(HFD+Ad-GFP组,n=10)、高脂-SFRP5过表达病毒组(HFD+Ad-SFRP5组,n=10),各组喂养13周后,利用定量PCR技术及Western-blot技术,分别检测小鼠肝脏糖异生关键酶磷酸烯醇式丙酮酸羧激酶(phosphoenolpyruvate carboxykinase,PEPCK)和葡萄糖-6-磷酸酶(glucose-6-phosphatase,G6Pase)mRNA及蛋白质水平的变化情况,以及肝脏经典胰岛素信号通路的改变。结果显示:高脂喂养组中,SFRP5表达上调可使肝脏糖异生指标PEPCK和G6Pase的mRNA及蛋白质相对表达水平均降低(P<0.05),而且SFRP5过表达可使肝脏经典胰岛素信号通路指标胰岛素受体(InsR)及蛋白激酶B(AKT)的磷酸化水平增高(P<0.05)。以上结果说明,C57BL/6J小鼠体内过表达SFRP5可能通过降低肝脏糖异生,增强胰岛素信号通路,从而改善机体胰岛素抵抗状态。

不同糖耐量人群血浆分泌型卷曲相关蛋白5水平与胰岛素抵抗的相关性研究

目的探讨不同糖耐量人群血浆分泌型卷曲相关蛋白5(SFRP5)水平变化及与APN、IR的关系。方法采用ELISA测定不同糖耐量人群血浆SFRP5和APN水平,分析血浆SFRP5与APN及相关代谢指标的关系。结果 T2DM、IGT组血浆SFRP5水平低于正常对照(NC)组[(42.99±20.89)vs(49.21±21.52)vs(78.48±23.72)μg/L,P<0.01]。肥胖者血浆SFRP5水平低于非肥胖者[(42.05±19.93)vs(67.72±26.48)μg/L,P<0.01]。相关性分析发现,血浆SFRP5水平与BMI、WHR、体内脂肪百分比(Fat%)、SBP、DBP、FPG、FIns、胰岛素抵抗指数(HOMA-IR)、HbA1c、TG、FFA呈负相关(P均<0.01),与APN、LDL-C呈正相关(P均<0.01)。结论血清SFRP5水平在新诊断T2DM患者和肥胖人群中明显降低,可能与IR有关。

MiR-1180 from bone marrow-derived mesenchymal stem cells induces glycolysis and chemoresistance in ovarian cancer cells by upregulating the Wnt signaling pathway

Background:Bone marrow-derived mesenchymal stem cells(BM-MSCs)play an important role in cancer development and progression.However,the mechanism by which they enhance the chemoresistance of ovarian cancer is unknown.Methods:Conditioned media of BM-MSCs(BM-MSC-CM)were analyzed using a technique based on microRNA arrays.The most highly expressed microRNAs were selected for testing their effects on glycolysis and chemoresistance in SKOV3 and COC1 ovarian cancer cells.The targeted gene and related signaling pathway were investigated using in silico analysis and in vitro cancer cell models.Kaplan-Merier survival analysis was performed on a population of 59 patients enrolled to analyze the clinical significance of microRNA findings in the prognosis of ovarian cancer.Results:MiR-1180 was the most abundant microRNA detected in BM-MSC-CM,which simultaneously induces glycolysis and chemoresistance(against cisplatin)in ovarian cancer cells.The secreted frizzled-related protein 1(SFRP1)gene was identified as a major target of miR-1180.The overexpression of miR-1180 led to the activation of Wnt signaling and its downstream components,namely Wnt5 a,β-catenin,c-Myc,and CyclinD1,which are responsible for glycolysis-induced chemoresistance.The miR-1180 level was inversely correlated with SFRP1 mRNA expression in ovarian cancer tissue.The overexpressed mi R-1180 was associated with a poor prognosis for the long-term(96-month)survival of ovarian cancer patients.Conclusions:BM-MSCs enhance the chemoresistance of ovarian cancer by releasing miR-1180.The released miR-1180 activates the Wnt signaling pathway in cancer cells by targeting SFRP1.The enhanced Wnt signaling upregulates the glycolytic level(i.e.Warburg effect),which reinforces the chemoresistance property of ovarian cancer cells.