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1.
APPL1(adaptor protein,phosphotyros ineinteraction,PH domain and leucine zipper containing 1)是近来发现的一种细胞内转接蛋白,是介导脂联素信号的调节蛋白,并可参与胰岛素等多种信号转导通路,与胰岛素抵抗、内皮细胞功能紊乱、肥胖及2型糖尿病等相关。有研究表明,低水平APPL1可预测2型糖尿病的发生危险,其可能参与胰岛素抵抗和2型糖尿病的病理生理过程。  相似文献   

2.
APPL1(adaptor protein,phosphotyrosine interaction,PH domain and leucine zipper containing 1)是近来发现的一种细胞内转接蛋白,是介导脂联素信号的调节蛋白,并可参与胰岛素等多种信号转导通路,与胰岛素抵抗、内皮细胞功能紊乱、肥胖及2型...  相似文献   

3.
APPL1和APPL2是与脂联素受体结合的两个衔接蛋白,并且能通过作用于脂联素受体(AdipoR1和AdipoR2)来调控脂联素信号通路。脂联素与脂联素受体基因变异均可导致胰岛素抵抗并增加肥胖风险。APPL1基因变异与体脂分布相关,而APPL2基因变异与肥胖等代谢疾病的相关性尚未有研究。  相似文献   

4.
目的:研究APPL1蛋白在人结直肠癌组织中的表达情况与临床病理参数的关系.方法:收集35例新鲜结直肠癌及27例正常直肠黏膜组织,采用免疫组织化学SP法和RT-PCR法检测APPL1在结直肠癌组织及正常直肠黏膜组织中的表达.采用半定量积分分级对该蛋白的表达强弱进行评分.结果:免疫组织化学和RT-PCR结果显示,APPL1蛋白在结直肠癌组织以及正常直肠黏膜组织中普遍表达,但该蛋白和相应的mRNA在癌组织中的表达高于对照组(P<0.05).在35例结直肠癌组织中,APPL1表达与分化程度、淋巴结转移、TNM分期相关(P<0.05),与性别、年龄、肿瘤大小、组织学类型无明显相关(P>0.05).结论:APPL1蛋白在结直肠癌组织中的表达上调,且该蛋白表达与患者肿瘤的分化程度、淋巴结转移情况以及TNM分期有关.APPL1有可能成为结直肠癌治疗的一个新靶点.  相似文献   

5.
目的探讨胃癌组织中APPL1和COX-2蛋白表达情况、二者相关情况及其与患者生存期的关系。方法应用免疫组织化学SP法检测83例经手术切除石蜡包埋存档胃癌组织中APPL1和COX-2蛋白的表达情况。结果胃癌组织中APPL1和COX-2表达阳性率分别为60.2%(50/83)、62.7%(52/83)。APPL1的表达与胃癌的浸润深度、淋巴结转移、TNM分期、组织学类型差异有统计学意义(P0.05);COX-2的表达与胃癌的浸润深度、淋巴结转移、TNM分期差异有统计学意义(P0.05),而与组织学类型差异无统计学意义(P0.05)。它们与肿瘤患者年龄、性别差异均无统计学意义(P0.05)。相关分析结果显示APPL1与COX-2表达呈正相关(P0.05)。生存曲线研究结果显示APPL1和COX-2表达与患者术后生存时间显著相关(P0.05)。结论 APPL1和COX-2表达程度与胃癌的浸润深度、淋巴结转移、TNM分期密切相关,影响患者的生存时间。  相似文献   

6.
目的:探讨APPL1在脂联素(adiponectin,ANP)拮抗SD乳鼠心肌细胞(neonatal cardiomyocytes)缺氧/复氧(H/R)损伤中的作用。方法: 分离SD乳鼠心肌细胞并培养。通过对培养的心肌细胞H/R损伤模拟缺血/再灌注(simulated ischemia reperfusion,SI/R)后,随机分为对照组、H/R组、H/R+APN组及H/R+APN+APPL1 RNAi组。采用四甲基偶氮唑蓝(MTT)比色法检测细胞的生存率,原位缺口末端标记(TUNEL)法检测细胞的凋亡,Western blot检测APPL1蛋白的表达。结果: 与对照组相比,H/R组吸光度值明显降低(P<0.01),凋亡指数(AI)显著上升(P<0.01)。与对照组和H/R组相比,H/R+APN组中APPL1的表达明显上升(P<0.05)。以RNAi抑制APPL1表达后,与H/R+APN组相比,H/R+APN+APPL1 RNAi组凋亡指数率(%)明显上升 [(28.32±4.13)% vs.(9.78±2.16)%,P<0.01]。结论: APN可显著抑制H/R损伤诱导的心肌细胞凋亡,促进心肌细胞存活,其拮抗作用与上调APPL1蛋白的表达相关。  相似文献   

7.
蛋白酪氨酸磷酸酶-1B(PTP-1B)通过对细胞内不同蛋白底物脱磷酸化参与不同的生理反应,在胰岛素、瘦素等多条细胞信号通路中发挥作用.因其参与多种生理、病理过程,近年来PTP-1B抑制剂的提取和研制成为相关疾病防治的新方向.  相似文献   

8.
目的探讨黑色素瘤特异性抗原(PRAME)、适应性蛋白L1(Adaptor protein containing PH domain,APPL1)在原发性肺腺癌中的表达及临床意义。方法收集2014年2月至2015年12月期间被我院收治的52例原发性肺腺癌患者手术切除的肺腺癌组织和癌旁组织为实验标本。采用RT-PCR技术检测组织标本中的PRAME、APPL1 mRNA表达量。结果肺腺癌组织中PRAME表达水平低于癌旁组织,差异有统计学意义(P0.05)。肺腺癌组织中APPL1表达水平高于癌旁组织,差异有统计学意义(P0.05)。随着肺腺癌病例病理分期的升高、肿瘤大小的增加、分化程度的降低,肺腺癌组织中PRAME mRNA表达减弱,APPL1 mRNA表达增强,此外,肺腺癌组织中PRAME、APPL1 mRNA水平与病例是否伴淋巴结转移有关。伴淋巴结转移的肺腺癌组织,PRAME mRNA水平低于未出现淋巴结转移的肺腺癌组织(P0.05),APPL1 mRNA水平高于未出现淋巴结转移的肺腺癌组织(P0.05)。原发性肺腺癌组织中PRAME、APPL1 mRNA表达量呈负相关(r=-0.412,P=0.007)。结论 PRAME在原发性肺腺癌组织中的表达水平低于癌旁组织,APPL1在原发性肺腺癌组织中的表达水平高于癌旁组织。PRAME、APPL1的表达与原发性肺腺癌组织的病理分期、肿瘤体积、分化程度及是否伴淋巴结转移有关。  相似文献   

9.
肝脏胰岛素抵抗的机制和后果   总被引:2,自引:0,他引:2  
肝脏作为胰岛素作用的主要靶器官,在维持空腹状态下内生性葡萄糖的产生和输出以及进食后葡萄糖的吸收、利用和存储等方面发挥重要作用.肝脏胰岛素抵抗主要是指胰岛素抑制肝脏葡萄糖输出能力下降,而细胞胰岛素抵抗则指细胞内胰岛素受体活化后参与细胞内信号传导的改变~([1]),可通过测定胰岛素刺激时的中间蛋白磷酸化、中介激酶活性改变和(或)调节靶基因表达或靶细胞功能改变来判断~([2]).  相似文献   

10.
目的观察苦酸通调方对胰岛素抵抗HepG2细胞内AMP活化蛋白激酶(AMPK)/乙酰辅酶A羟化酶(ACC)/固醇调节元件结合蛋白(SREBP)-1信号分子的影响。方法通过0.25 mmol/L棕榈酸联合30 mmol/L高糖孵育24 h诱导HepG2胰岛素抵抗细胞模型。噻唑蓝(MTT)比色法测定细胞存活率确定给药浓度。荧光标记2-脱氧葡萄糖(2-NBDG)法检测细胞葡萄糖摄取能力,油红O染色观察细胞内脂质累积情况,三酰甘油试剂盒检测细胞内三酰甘油含量,Western印迹法检测细胞内AMPK、ACC、SREBP-1的蛋白表达水平。结果与模型组相比,苦酸通调方干预后,呈剂量依赖性增加胰岛素抵抗HepG2细胞的葡萄糖摄取量,减少细胞内三酰甘油含量(P<0.05),上调AMPK、ACC蛋白磷酸活化水平,减少SREBP-1蛋白表达(P<0.05)。结论苦酸通调方可能通过调控AMPK/ACC/SREBP-1信号转导过程,增强肝细胞葡萄糖摄取能力,减少细胞内三酰甘油蓄积,从而改善HepG2细胞的胰岛素抵抗状态。  相似文献   

11.
APPL1 is an adaptor protein that binds to both AKT and adiponectin receptors and is hypothesised to mediate the effects of adiponectin in activating downstream effectors such as AMP-activated protein kinase (AMPK). We aimed to establish whether APPL1 plays a physiological role in mediating glycogen accumulation and insulin sensitivity in muscle and the signalling pathways involved. In vivo electrotransfer of cDNA- and shRNA-expressing constructs was used to over-express or silence APPL1 for 1 week in single tibialis cranialis muscles of rats. Resulting changes in glucose and lipid metabolism and signalling pathway activation were investigated under basal conditions and in high-fat diet (HFD)- or chow-fed rats under hyperinsulinaemic-euglycaemic clamp conditions. APPL1 over-expression (OE) caused an increase in glycogen storage and insulin-stimulated glycogen synthesis in muscle, accompanied by a modest increase in glucose uptake. Glycogen synthesis during the clamp was reduced by HFD but normalised by APPL1 OE. These effects are likely explained by APPL1 OE-induced increase in basal and insulin-stimulated phosphorylation of IRS1, AKT, GSK3β and TBC1D4. On the contrary, APPL1 OE, such as HFD, reduced AMPK and acetyl-CoA carboxylase phosphorylation and PPARγ coactivator-1α and uncoupling protein 3 expression. Furthermore, APPL1 silencing caused complementary changes in glycogen storage and phosphorylation of AMPK and PI3-kinase pathway intermediates. Thus, APPL1 may provide a means for crosstalk between adiponectin and insulin signalling pathways, mediating the insulin-sensitising effects of adiponectin on muscle glucose disposal. These effects do not appear to require AMPK. Activation of signalling mediated via APPL1 may be beneficial in overcoming muscle insulin resistance.  相似文献   

12.
AIMS: APPL1 (adaptor protein containing PH domain, PTB domain and leucine zipper motif 1) is the first identified cytosolic protein that directly binds to adiponectin receptors and mediates cellular responses to adiponectin. We set out to determine whether genetic variation within the APPL locus (encoding APPL1) contributes to insulin resistance, changes in lipid metabolism or inflammatory parameters in a healthy White population. METHODS: We genotyped 640 healthy subjects with and without a family history of diabetes for the four single nucleotide polymorphisms (SNPs) rs6774584, rs3087684, rs17791685 and rs528035 and performed correlational analyses with metabolic and inflammatory traits. RESULTS: SNPs rs6774584, rs3087684, rs17791685 and rs528035 are representative of the four blocks of high linkage disequilibrium covering a 78-kb genomic locus that harbours the APPL gene. None of these SNPs correlated with anthropometric data (gender, age, body mass index, body fat, waist-hip ratio) or with family history of diabetes. Furthermore, no correlations were found with parameters of insulin sensitivity or insulin secretion. None of the SNPs was correlated with ectopic lipid content or with plasma lipids (non-esterified fatty acids, glycerol, triglycerides, total cholesterol, high-density lipoprotein-, low-density lipoprotein-cholesterol). Moreover, no correlations were detected with leucocyte measures or plasma concentrations of C-reactive protein, monocyte chemoattractant protein 1, interleukin 6 or tumour necrosis factor-alpha. Finally, diplotypes derived from these SNPs did not reveal correlations with insulin sensitivity, insulin secretion, lipid measures or inflammatory parameters either. CONCLUSIONS: We conclude that genetic variation within the APPL locus may not play a major role in the development of prediabetes phenotypes.  相似文献   

13.
Insulin resistance and defective insulin secretion are the two major features of type 2 diabetes. The adapter protein APPL1 is an obligatory molecule in regulating peripheral insulin sensitivity, but its role in insulin secretion remains elusive. Here, we show that APPL1 expression in pancreatic β cells is markedly decreased in several mouse models of obesity and diabetes. APPL1 knockout mice exhibit glucose intolerance and impaired glucose-stimulated insulin secretion (GSIS), whereas transgenic expression of APPL1 prevents high-fat diet (HFD)-induced glucose intolerance partly by enhancing GSIS. In both pancreatic islets and rat β cells, APPL1 deficiency causes a marked reduction in expression of the exocytotic machinery SNARE proteins (syntaxin-1, synaptosomal-associated protein 25, and vesicle-associated membrane protein 2) and an obvious decrease in the number of exocytotic events. Such changes are accompanied by diminished insulin-stimulated Akt activation. Furthermore, the defective GSIS and reduced expression of SNARE proteins in APPL1-deficient β cells can be rescued by adenovirus-mediated expression of APPL1 or constitutively active Akt. These findings demonstrate that APPL1 couples insulin-stimulated Akt activation to GSIS by promoting the expression of the core exocytotic machinery involved in exocytosis and also suggest that reduced APPL1 expression in pancreatic islets may serve as a pathological link that couples insulin resistance to β-cell dysfunction in type 2 diabetes.  相似文献   

14.

Aims/hypothesis

Adaptor protein, phosphotyrosine interaction, pleckstrin homology domain and leucine zipper containing 1 (APPL1) is an adapter protein that positively mediates adiponectin signalling. Deficiency of APPL1 in the target tissues of insulin induces insulin resistance. We therefore aimed, in the present study, to determine its role in regulating pancreatic beta cell function.

Methods

A hyperglycaemic clamp test was performed to determine insulin secretion in APPL1 knockout (KO) mice. Glucose- and adiponectin-induced insulin release was measured in islets from APPL1 KO mice or INS-1(832/13) cells with either APPL1 knockdown or overproduction. RT-PCR and western blotting were conducted to analyse gene expression and protein abundance. Oxygen consumption rate (OCR), ATP production and mitochondrial membrane potential were assayed to evaluate mitochondrial function.

Results

APPL1 is highly expressed in pancreatic islets, but its levels are decreased in mice fed a high-fat diet and db/db mice compared with controls. Deletion of the Appl1 gene leads to impairment of both the first and second phases of insulin secretion during hyperglycaemic clamp tests. In addition, glucose-stimulated insulin secretion (GSIS) is significantly decreased in islets from APPL1 KO mice. Conversely, overproduction of APPL1 leads to an increase in GSIS in beta cells. In addition, expression levels of several genes involved in insulin production, mitochondrial biogenesis and mitochondrial OCR, ATP production and mitochondrial membrane potential are reduced significantly in APPL1-knockdown beta cells. Moreover, suppression or overexproduction of APPL1 inhibits or stimulates adiponectin-potentiated GSIS in beta cells, respectively.

Conclusions/interpretation

Our study demonstrates the roles of APPL1 in regulating GSIS and mitochondrial function in pancreatic beta cells, which implicates APPL1 as a therapeutic target in the treatment of type 2 diabetes.  相似文献   

15.
16.
Tian L  Luo N  Zhu X  Chung BH  Garvey WT  Fu Y 《Atherosclerosis》2012,221(1):66-75
ObjectiveAdiponectin is an adipokine that exerts anti-inflammatory and anti-atherogenic effects during macrophage transformation into foam cells. To further understand the signaling pathways of adiponectin involved in macrophage foam cell transformation, we investigated the roles of two adiponectin receptors (AdipoR1 and AdipoR2) and their downstream adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 1 (APPL1) in mediating adiponectin action on foam cell transformation.Methods and ResultsTransfections were performed to overexpress or knockdown AdipoR1 or AdipoR2 genes in human THP-1 monocytes. Lentiviral-shRNAs were also used to knockdown APPL1 gene in these cells. Foam cell transformation was induced via exposure to oxidized low-density lipoprotein (oxLDL). Our results showed that both AdipoR1 and AdipoR2 were critical for transducing the adiponectin signal that suppresses lipid accumulation and inhibits transformation from macrophage to foam cell. However, AdipoR1 and AdipoR2 were found to have differential effects in diminishing proinflammatory responses. While AdipoR1 was required by adiponectin to suppress tumor necrosis factor alpha (TNFα) and monocyte chemotactic protein 1 (MCP-1) gene expression, AdipoR2 served as the dominant receptor for adiponectin suppression of scavenger receptor A type 1 (SR-AI) and upregulation of interleukin-1 receptor antagonist (IL-1Ra). Knockdown of APPL1 significantly abrogated the ability of adiponectin to inhibit lipid accumulation, SR-AI and nuclear factor-κB (NF-κB) gene expression, and Akt phosphorylation in macrophage foam cells.ConclusionsIn current studies, we have demonstrated that adiponectin's abilty to suppress macrophage lipid accumulation and foam cell formation is mediated through AdipoR1 and AdipoR2 and the APPL1 docking protein. However, AdipoR1 and AdipoR2 exhibited a differential ability to regulate inflammatory cytokines and SR-A1. These novel data support the idea that the adiponectin-AdipoR1/2-APPL1 axis may serve as a potential therapeutic target for preventing macrophage foam cell formation and atherosclerosis.  相似文献   

17.
A number of signaling proteins have been demonstrated to interact with follicle stimulating hormone (FSH) receptor (FSHR), including APPL1, 14-3-3τ and Akt2. To further define the repertoire of proteins involved in FSH-induced signal transduction, several signaling and adapter proteins were examined for the ability to associate with FSHR. This report shows that, in addition to APPL1, FSHR interacts with FOXO1a and APPL2. Moreover, APPL1 and APPL2 associate with one another via the N-terminus of APPL1, presumably via the Bin-Amphiphysin-Rvs (BAR) domain. The interactions between FSHR and APPL2 and between FSHR and FOXO1a evidently are distinct since FOXO1a does not associate with either APPL1 or with APPL2. Though APPL1 and APPL2 show some similarity in primary sequence, APPL1 associates with Akt2, whereas APPL2 does not. This is the first documented difference in function between APPL1 and APPL2. These results suggest that FSHR, APPL1, APPL2, Akt2 and FOXO1a are organized into distinct scaffolding networks in the cell. Accordingly, the spatial organization of signaling and adapter proteins with FSHR likely facilitates and finely regulates the signal transduction induced by FSH.  相似文献   

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