动脉粥样硬化进程中脂联素的研究进展

脂联素（adiponeefin）是由脂肪细胞分泌的一种特殊血浆蛋白，正常人体中血浆脂联素含量丰富。体外研究发现脂联素抑制备种细胞黏附分子的表达；细胞培养证实脂联素可抑制血管细胞及平滑肌的增殖，并抑制单核一巨噬细胞的迁移及向泡沫细胞的转化；动物实验发现脂联素基因缺陷小鼠动脉内膜明显增厚：临床研究发现肥胖、糖尿病、代谢综合征、冠心病患者血浆脂联素水平明显下降。种种迹象表明脂联素具有抗动脉粥样硬化的作用。     

尿脂联素——2型糖尿病血管损害的新标志物

脂联素是脂肪细胞衍生的血管活性肽（30kDa）,通过降低血管炎症、泡沫细胞形成和细胞黏附,对血管内皮细胞产生抗炎和抗动脉粥样化作用。最近研究报道,在非糖尿病肾脏的肾小球毛细血管和肾内小动脉的内皮细胞表面有脂联素,在糖尿病肾小球毛细血管应激时,来自内皮细胞表面的脂联素被蛋白水解,由高级脂联素复合物降解为单聚体（～28kDa）、双聚体（～56kDa）和三聚体（～68kDa）而出现在尿液内,推测脂联素在尿内出现反映2型糖尿病（T2DM）肾小球血管早期损害甚于代谢改变时伴随的血脂联素变化。     

脂联素在冠状动脉粥样硬化性心脏病中的重要作用

脂联素是由脂肪细胞等分泌的一种具有心血管保护作用的细胞因子。脂联素可以通过多种信号通路发挥抗炎、抗动脉硬化、抗栓、抗纤维化、保护血管内皮及调节糖脂代谢的作用。     

2型糖尿病合并糖尿病肾病脂联素水平变化及与血管内皮功能的关系

目的探讨糖尿病肾病患者血清脂联素水平的变化,及与血管内皮功能的关系。方法 50例无明显临床大血管并发症的2型糖尿病患者,按24 h尿白蛋白排出量分为正常白蛋白尿组、微量白蛋白尿组及大量白蛋白尿组。检测血清脂联素、可溶性血管细胞黏附分子1、生物化学指标、肱动脉内皮依赖性舒张功能(FMD)、含服硝酸甘油后肱动脉内皮依赖性舒张功能(NID)、心脏结构参数及颈动脉内膜-中膜厚度。结果大量白蛋白尿组脂联素水平是正常白蛋白尿组的4倍,是微量白蛋白尿组的2倍(P<0.01和P<0.05)。微量白蛋白尿组脂联素水平比正常白蛋白尿组升高(P<0.05)。脂联素/血肌酐在三组中有同样的变化(均P<0.05)。大量白蛋白尿组和微量白蛋白尿组可溶性血管细胞黏附分子1均高于正常白蛋白尿组(P<0.01和P<0.05)。大量白蛋白尿组FMD、NID随脂联素水平的增加而下降(P<0.05)。颈动脉内膜-中膜厚度在三组间无统计学差异。脂联素与可溶性血管细胞黏附分子1、24 h尿白蛋白排出量、血肌酐、左心室后壁厚度、内膜-中膜厚度呈正相关(r值分别为0.338、0.704、0.470、0.331、0.324,P<0.05),与FMD、NID呈显著负相关(r值为-0.397、-0.413,P<0.01)。结论糖尿病肾病伴随高脂联素血症,且与血管内皮功能损害密切相关。脂联素可作为糖尿病肾病患者早期血管内皮功能障碍的预测指标。     

脂联素与冠心病及其危险因素的关系

人体的脂肪细胞不仅是储能细胞，也能分泌许多信号蛋白和细胞因子，如C-反应蛋白、肿瘤坏死因子（tumor necrosis factor，TNF）-α、白介素（interleukin，IL）-6、血管内皮生长因子、血管紧张素原、纤溶酶原激活物抑制剂-1（plasminogen activator inhibitor，PAI-1）、脂联素（adiponectin）等，具有广泛的生物活性。其中脂联素在机体代谢过程中具有许多重要作用，并与多种疾病有关，已有研究报道显示脂联素水平与冠心病的发生和发展呈负相关，低脂联素血症是冠心病的独立危险因素。另外高血压、糖尿病，脂代谢紊乱也是冠心病的主要危险因素。因此脂联素与冠心病及其危险因素关系的相关研究是目前的热点之一。     

脂联素对结肠癌HT-29细胞的增殖及凋亡研究

目的探讨脂联素对结肠癌HT-29细胞的增殖、凋亡的影响。方法以不同浓度脂联素干预细胞,MTT法检测细胞增殖能力;AnnexinV／PI双染后流式细胞仪检测细胞凋亡。结果随着脂联素浓度的不断升高和培养时间的延长,HT-29细胞的生长逐渐受到抑制,脂联素可以诱导细胞凋亡。结论脂联素可抑制HT-29细胞增殖,诱导细胞凋亡。     

脂联素与心血管疾病的研究现状与展望

肥胖与心血管疾病及代谢紊乱密切相关。脂联素是一种脂肪源性血浆蛋白,在与肥胖相关的代谢紊乱及疾病中含量降低,低脂联素水平与肥胖相关的心血管疾病危险性增加有关。有研究表明,脂联素可直接作用于心肌及血管细胞发挥作用,可通过多种机制保护心血管系统。其中主要包括调节一磷酸腺苷活性蛋白酶介导的信号通路、抑制炎症与促进内皮细胞功能等。脂联素所共有的调节代谢、抗炎及血管保护、心肌保护作用,可为临床治疗代谢综合征性心血管疾病,提供新的干预靶点和治疗思路。     

脂联素对大鼠原代Kupffer细胞白细胞介素10表达的影响

目的本研究观察外源性脂联素对体外培养的大鼠原代Kupffer细胞白细胞介素（IL）-10表达的调节作用,以阐明脂联素的抗炎作用机制。方法通过两步胶原酶灌流、密度梯度离心和2 h选择性贴壁方法分离纯化大鼠肝脏Kupffer细胞。酶联免疫吸附试验方法检测脂联素作用下原代Kupffer细胞上清液中IL-10的表达水平。荧光定量PCR法检测脂联素作用下原代Kupffer细胞IL-10 mRNA表达。结果 0.5、1.0、1.5μg/ml脂联素处理Kupffer细胞4、8、12、16 h,与对照组相比,同一浓度的脂联素随着培养时间的延长,Kupffer细胞IL-10分泌逐渐增加;而同一作用时间下,随着脂联素浓度的增加,Kupffer细胞IL-10分泌量并没有逐渐增加。1.0和1.5μg/ml脂联素作用Kupffer细胞16 h,IL-10基因表达量与对照组相比显著增加,各处理组间无明显差异。结论脂联素可上调大鼠原代Kupffer细胞IL-10的表达,这可能是其抗炎作用机制之一。     

2型糖尿病患者血浆脂联素、同型半胱氨酸水平与血管内皮功能的关系

目的探讨2型糖尿病患者的血浆脂联素、同型半胱氨酸（Hcy）水平及其与血管的内皮功能的关系。方法选择2型糖尿病患者56例和健康体检者48例为对照组,用酶联免疫吸附法（ELISA）测定患者血浆Hcy和脂联素水平,用Celermajer法测定血管内皮功能。结果2型糖尿病组血浆Hcy水平明显高于对照组（P〈0．01）;而血浆脂联素水平、内皮依赖性血管舒张功能（EDD）及非内皮依赖性血管舒张功能（EID）分别低于对照组（P〈0．01）。EED与血浆Hcy呈负相关,而与脂联素呈正相关。结论2型糖尿病患者血浆Hcy水平升高,而脂联素水平减低,提示血浆Hcy升高以及脂联素的降低是2型糖尿病内皮功能损伤的重要的因素,测定血浆Hcy、脂联素和EDD可以反映2型糖尿病患者血管病变情况。     

脂联素与血管内皮细胞功能障碍的相关性

代谢综合征的组成成份致冠状动脉粥样硬化性心脏病发生发展的内在机制尚待进一步研究。脂联素作为一种脂肪细胞因子,与内皮依赖性血管舒张功能呈独立正相关,并且是后者的独立决定因素;通过多重信号传导途径上调内皮细胞一氧化氮合成酶活性、增加一氧化氮生成,抑制内皮细胞氧化应激反应、降低细胞损伤程度,阻断内皮细胞炎症信号传导、减轻血管炎症反应。因此,脂联素可能是联系代谢综合征与心血管疾病的枢纽,可以考虑利用脂联素改善代谢综合征患者的血管内皮功能,进而预防或延缓心血管疾病的发生发展。     

Hypoadiponectinemia: A common basis for diseases associated with overnutrition

Adiponectin is a plasma protein derived from adipose tissue, which we discovered from a human adipose cDNA project. Adiponectin exists in circulating plasma at concentrations ranging from 4 to 30 μg/mL, which is much higher than the concentrations of various other hormones and cytokines. Adiponectin has a sticky nature, binding to collagen I, III, and V, which are present in vascular intima. Adiponectin exhibits various antiatherogenic effects on vascular cells, suppressing the expression of adhesion molecules in vascular endothelial cells, proliferation of smooth muscle cells, and cholesteryl-ester accumulation in macrophages. However, its plasma levels are low in subjects with excess intra-abdominal fat. Adiponectin also has antidiabetic properties, and plasma adiponectin levels correlate positively with insulin sensitivity. Several clinical studies have demonstrated that hypoadiponectinemia is a risk factor for new-onset diabetes. Recent studies suggest that hypoadiponectinemia may partly contribute to the development of salt-sensitive hypertension and hypertensive heart failure, and can be also a risk factor for overnutrition-related cancers such as breast, colon, uterine, and prostate cancers. Hypoadiponectinemia might be at least in part the molecular basis of various diseases associated with overnutrition.     

脂联素与骨代谢

脂肪细胞分泌多种生物活性分子,统称脂肪细胞因子。脂联素是新近发现的由脂肪细胞分泌的胶原样蛋白质。近年的研究表明,脂联素及其受体可在成骨细胞表达,脂联素呈剂量与时间依赖方式诱导p38丝裂原活化蛋白激酶(MAPK)及c-Jun氨基末端激酶(JNK)的活性,促进成骨细胞的增殖与分化,影响破骨细胞的分化与活性。对脂联素的深入研究有助于进一步了解肥胖与骨代谢之间的关系,为同时防治骨质疏松与动脉硬化提供新思路。     

脂联素和心血管疾病关系的研究进展

探讨脂联素通过对血管内皮细胞及其产生的一氧化氮对血管内皮的功能产生影响,在动脉粥样硬化、冠心病、高血压等心血管疾病方面起到重要的调节作用;血浆脂联素水平低已逐渐认为是心血管疾病的独立危险因素。     

脂联素对泡沫细胞三磷酸腺苷结合盒转运体A1表达及细胞内胆固醇含量的影响

目的通过研究脂联素对细胞内胆固醇外流的影响以及三磷酸腺苷结合盒转运子A1的功能变化,探讨其抗动脉粥样硬化作用的可能机制。方法以THP-1来源的泡沫细胞模型为研究对象,用脂联素进行体外干预;采用逆转录聚合酶链反应、酶联免疫吸附试验和高效液相色谱等方法测定干预前后三磷酸腺苷结合盒转运子A1表达和细胞内胆固醇含量的变化。结果脂联素在体外上调泡沫细胞三磷酸腺苷结合盒转运子A1mRNA和蛋白的表达,与载脂蛋白A1联合作用还能进一步增加细胞内胆固醇的流出。脂联素单独作用促进细胞内胆固醇酯转化为游离胆固醇。结论脂联素上调泡沫细胞三磷酸腺苷结合盒转运子A1表达,并促进其介导的细胞内游离胆固醇的外流;脂联素还能促进细胞内胆固醇酯的水解。     

脂联素及其临床应用前景

脂联素是脂肪组织分泌的一种细胞因子,通过增加外周组织对葡萄糖和脂肪酸的摄取及利用,抑制肝糖输出,调节糖脂代谢;同时还可以在中枢影响食欲及能量消耗,调节能量代谢.此外脂联素还有抗炎、抗动脉粥样硬化、抑制肿瘤细胞增生及促进其凋亡等作用.研究发现血浆脂联素可作为糖尿病、代谢综合征、冠心病、肿瘤等疾病危险因素的预测指标,同时脂联素也可用于相关疾病的治疗.     

脂联素及其临床应用前景

脂联素是脂肪组织分泌的一种细胞因子,通过增加外周组织对葡萄糖和脂肪酸的摄取及利用,抑制肝糖输出,调节糖脂代谢;同时还可以在中枢影响食欲及能量消耗,调节能量代谢.此外脂联素还有抗炎、抗动脉粥样硬化、抑制肿瘤细胞增生及促进其凋亡等作用.研究发现血浆脂联素可作为糖尿病、代谢综合征、冠心病、肿瘤等疾病危险因素的预测指标,同时脂联素也可用于相关疾病的治疗.     

The role of adiponectin for immune cell function in metabolic diseases

Adiponectin, as an indispensable regulator of the immune system, is the most abundant adipokine and is mainly produced by white adipose tissue. Adiponectin mediates the positive effects on systemic metabolism by regulating associated downstream signalling pathways; however, accumulating evidence shows that adiponectin plays an important role in regulating the function of innate and adaptive immune cells in the development of obesity and its related diseases. In this review, we focus on the biological function of adiponectin in regulating innate and adaptive immunity and outline the key role of adiponectin in various metabolic diseases, which will highlight a potential direction for adiponectin-based therapeutic interventions for metabolic diseases.     

Adiponectin and its receptors in non-alcoholic steatohepatitis

BACKGROUND: Adiponectin, an adipocyte derived polypeptide, has been shown to alleviate steatosis and inflammation in mice with non-alcoholic fatty liver disease. AIM: In the present study, we wished to define liver expression of adiponectin and its receptors in morbidly obese patients undergoing bariatric surgery. Patients with non-alcoholic steatohepatitis (NASH) or simple steatosis were investigated to test whether dysregulation of this system might be involved in these disorders. PATIENTS AND METHODS: Liver mRNA expression of adiponectin and its recently cloned receptors RI and RII (adipoRI and adipoRII) were analysed by fluorescence based real time polymerase chain reaction in 13 patients with NASH and nine with simple steatosis. Adiponectin and adipoRII protein expression were assessed by immunohistochemistry in a subgroup of patients. RESULTS: Adiponectin and adipoRII mRNA expression were significantly reduced in liver biopsies of patients with NASH compared with simple steatosis while no difference was found in adipoRI mRNA expression. In NASH, adipoRII mRNA expression was negatively correlated with serum aspartate aminotransferase levels, serum alanine aminotransferase levels, and grade of fibrosis. Liver adiponectin protein expression was mainly found in endothelial cells of portal vessels and liver sinusoids whereas adipoRII expression was seen in hepatocytes only. Adiponectin and adipoRII staining were lower in biopsies of subjects with NASH compared with simple steatosis. CONCLUSION: Reduced hepatic expression of adiponectin and adipoRII might be of pathophysiological relevance in non-alcoholic fatty liver diseases.     

Adiponectin and hypertension

Adipose tissue secretes a variety of bioactive molecules, also known as adipocytokines or adipokines. Obesity, in particular, visceral fat accumulation, is implicated in the dysregulated secretion of adipocytokines, which can contribute to the development of metabolic syndrome and cardiovascular diseases. Adiponectin is an adipocytokine that is exclusively secreted from adipose tissue, but its plasma levels are reduced in obese subjects, especially those with visceral fat accumulation. Adiponectin has a variety of protective properties against obesity-linked complications, such as hypertension, metabolic dysfunction, atherosclerosis, and ischemic heart disease. Adiponectin exerts the beneficial effects on vascular disorders by directly affecting components of vascular tissue. This review will discuss clinical and experimental findings that examine the role of adiponectin in regulation of hypertension and vascular function.     

Role of adiponectin in regulating ovarian theca and granulosa cell function

Adiponectin is an adipokine that has been implicated in insulin resistance, a condition associated with polycystic ovarian syndrome in humans, but whether adiponectin can directly affect ovarian theca or granulosa cell function is unknown. Therefore, to determine the effects of adiponectin on proliferation, steroidogenesis and gene expression of large-follicle theca and granulosa cells, experiments were conducted using bovine ovarian cell cultures. RT-PCR was used to elucidate the effects of adiponectin on gene expression of CYP11A1 and LH receptor (LHR) in large-follicle theca and granulosa cells, as well as expression of CYP17A1 in theca cells and CYP19A1 in granulosa cells. Adiponectin decreased (P<0.05) insulin-induced progesterone and androstenedione production as well as attenuated IGF-I-induced LHR, CYP11A1, and CYP17A1 gene expression in theca cells. In contrast, adiponectin decreased (P<0.05) LHR mRNA abundance in granulosa cells but did not affect steroidogenic enzyme gene expression in granulosa cells. Adiponectin had no effect (P>0.10) on proliferation of large-follicle theca cells. RT-PCR also revealed that abundance of mRNA for the adiponectin receptor (ADIPOR2) was greater (P<0.05) in large-follicle than in small-follicle theca cells and did not significantly differ between small- and large-follicle granulosa cells. In cultured theca cells, LH increased (P<0.05) and IGF-I decreased (P<0.05) ADIPOR2 mRNA abundance. These results indicate that the inhibitory effects of adiponectin on steroidogenesis are primarily localized to theca cells and that the response of theca cells to adiponectin (i.e., ADIPOR2) may be regulated by LH and IGF-I.