脂肪因子Chemerin与代谢相关疾病的研究进展

2018-01-15 01:25郑晓娟安秀琴刘近春
中国临床医学 2018年1期
关键词:脂肪组织受体脂肪

郑晓娟, 安秀琴, 杨 斐, 刘近春

山西医科大学第一医院消化内科,太原 030001

Chemerin是一种新近发现的脂肪因子,是G蛋白偶联受体人趋化因子受体 1(CMKLR1/ chemR23)的配体配体[1]。Chemerin在肝脏和脂肪组织中高表达,其循环水平与体质指数(BMI)、三酰甘油、血压等密切相关[2]。 Chemerin表达、分泌、活化及信号转导等受到严格调控。Chemerin一般以其不活跃的前体形式prochemerin存在于循环,当机体发生凝血、纤溶、炎症级联反应等时,其前体经蛋白酶水解为具有生物活性的chemerin[3]。Chemerin通过与其受体CMKLR1、G蛋白偶联受体(GPR1)、C-C类趋化因子受体样蛋白2(CCRL2)结合而发挥作用。

代谢综合征(metabolic syndrom, MS)主要临床改变包括中心性肥胖、糖尿病或糖损害、高血压和血脂异常。胰岛素抵抗(IR)是MS的常见病理生理基础。随着生活方式和饮食结构的改变,MS的患病率增加[4]。在人体中,循环chemerin水平是与MS多个组分密切相关,包括BMI、三酰甘油、高密度脂蛋白胆固醇(HDL-C)和血压等。

1 Chemerin与炎症的关系

在多种炎症相关疾病中,循环chemerin水平增高[5-8]。Chemerin最初是以炎症因子被发现的[9-10]。研究[3]发现,chemerin可促进表达CMKLR1的白细胞趋化,如未成熟的树突细胞、未成熟的髓系树突细胞、巨噬细胞和自然杀伤细胞等,且chemerin可激活树突细胞。Luangsay等[11]研究发现,在急性病毒性肺炎小鼠模型中,chemR23可抑制肺部炎症反应并增强肺部抗病毒能力;在酵母聚糖诱导的小鼠腹膜炎中,用chemerin进行干预后,促炎介质表达减少、中性粒细胞减少63%、单核巨噬细胞减少62%[5]。Parlee等[12]研究表明,肿瘤坏死因子α(TNF-α)可促进脂肪细胞合成和分泌prochemerin。Chemerin在巨噬细胞高表达[13],而血清chemerin与促炎因子白细胞介素6(IL-6)、TNF-α等正相关[14]。在炎症性肠病患者中,循环中chemerin水平增高,说明chemerin可能在溃疡性结肠炎以及克罗恩病中发挥促炎效应[6]。Luangsay等[11]在小鼠急性肺炎模型中发现,chemerin具有促炎和抗炎双重作用。Rourke[15]指出,chemerin作为脂肪生成、糖代谢和炎症的重要调节物,在巨噬细胞浸润脂肪组织中起重要作用。Chemerin通过其受体表现抗炎特性或者促炎特性,这可能与在不同炎症阶段,chemerin不同同分异构体所占主导地位有关。

2 Chemerin与肥胖的关系

研究[16-17]表明,与肥胖相关的代谢性疾病由炎症细胞(主要为脂肪组织中的巨噬细胞)聚集加重慢性低度炎症,释放炎症介质,进而导致脂肪组织炎症进展。这种低度炎症是IR和相关代谢并发症如2型糖尿病和非酒精性脂肪性肝病(NAFLD)发生发展的基础。而chemerin由白色脂肪组织分泌,与脂肪含量和分布密切相关,并可影响脂肪组织的分化以及参与低级炎症反应。

Chemerin已被证明与肥胖密切相关[17]。Chemerin影响肥胖的可能机制如下:首先,chemerin能促进脂肪细胞分化与代谢;其次,chemerin在一定程度上能抑制脂肪分解;此外,chemerin可能参与炎症免疫反应。研究[18]表明,肥胖人或肥胖动物中,循环chemerin水平均提高,且与MS的各指标正相关。肥胖患者脂肪组织中聚集着大量表达CMKLR1的白细胞,包括未成熟的树突细胞、 巨噬细胞和自然杀伤细胞[19]。研究[20]表明,血清chemerin水平与BMI正相关。Fatima等[7]发现,肥胖患者中BMI大于25 kg/m2者的血清chemerin水平明显高于BMI低于25 kg/m2患者。研究[21]发现,相比消瘦人群,在肥胖患者中,尤其是伴有IR的患者中,chemerin受体CMKLR1的表达水平上升;而且CMKLR1高表达的个体腹部脂肪堆积更多,代谢标志物水平上升。动物实验[22]显示,在糖耐量正常的动物中,内脏脂肪chemerin的基因表达比皮下脂肪更多,而内脏脂肪堆积与肥胖的相关性更为显著。血清chemerin与腰臀比正相关[23]。磁共振量化内脏脂肪后发现,内脏脂肪与2型糖尿病高危个体编码chemerin的RARRES2基因变异密切相关[24]。另外,研究[18,25]发现,在接受减肥手术的病态肥胖(BMI>40 kg/m2或 BMI≥35 kg/m2,合并危及生命的心肺疾病或严重糖尿病)患者中,chemerin血清浓度的持续降低与体质量减轻及代谢参数的改善相关。

3 Chemerin与多囊卵巢综合征(polycystic ovary syndrome,PCOS)的关系

PCOS是女性常见的内分泌代谢疾病,5%~10%的育龄妇女患有此病[26]。Chemerin可能在PCOS的发生和发展中起重要作用。研究[8]表明,与对照组相比,高雄激素PCOS患者血清chemerin显著提高。在肥胖女性和患有PCOS的患者中发现,血清中chemerin的水平较高,而经二甲双胍治疗后降低[8]。动物实验[27]表明,重组chemerin可抑制正常小鼠颗粒细胞基础雌二醇的分泌以及卵泡刺激素诱导的孕酮和雌二醇的分泌,表明chemerin及其受体在卵泡的生长成熟中发挥重要作用。在双氢睾酮诱导的PCOS小鼠模型中,CMKLR1缺乏可显著改善PCOS小鼠临床症状及卵巢基因的表达,较野生型小鼠能维持相对正常的发情周期,也有更高的雌激素和孕激素水平[28],这可能与chemerin可以抑制类固醇的分泌有关。类固醇生成的关键酶,如急性调节蛋白、细胞色素P450、3β-类固醇脱氢酶等在CMKLR1敲除的小鼠中表达都下调[29]。此外,研究[30]发现,CMKLR1可由人类子宫产生和表达,可出现在蜕膜细胞、基质细胞及绒毛外细胞滋养细胞,而非蜕膜内皮细胞;CMKLR1在子宫蜕膜化时上调,表明其在怀孕早期血管重建中扮演重要角色。

4 Chemerin与糖尿病的关系

脂肪组织通过释放各种脂肪因子影响内分泌活动或参与机体炎症,而炎症是IR和糖尿病的发展的核心环节。Chemerin在这个过程中发挥重要作用[31]。Weigert等[32]发现,在2型糖尿病患者中,C反应蛋白高的患者chemerin水平更高。Chemerin可通过介导IR[24]及调节肝细胞、肌细胞等靶组织对胰岛素的敏感性[33]来影响糖脂代谢及炎症过程。体外研究[34]中发现,胰岛素也可影响chemerin的分泌,长时间胰岛素注射可使人类脂肪组织外植体中chemerin的分泌增加。经二甲双胍或吡格列酮治疗后,糖尿病患者血浆chemerin水平降低[35]。其中,吡格列酮可通过作用于过氧化物酶体增殖物激活受体γ (PPAR-γ)来改善血糖水平,而PPAR-γ参与调节脂肪细胞脂质沉积及细胞因子分泌[32]。

然而,chemerin与2型糖尿病是否相关仍有争议。研究[36]表明,在3T3-L1脂肪细胞中,chemerin可通过胰岛素信号通路影响葡萄糖的摄取,表明chemerin可调节脂肪组织的胰岛素敏感性,增加chemerin浓度,胰岛素浓度下降。但该研究也表明,患者空腹胰岛素(FSI)与血清chemerin正相关,即需要增加chemerin来增强胰岛素敏感性。因此,chemerin与胰岛素的关系需要进一步的探索。

5 Chemerin与肾脏疾病的关系

IR可促进慢性肾病的发生,即使在肾小球滤过率正常的轻到中度慢性肾脏病患者中,IR也非常普遍。氧化应激、内质网应激、炎症、维生素D缺乏等都可通过抑制胰岛素受体通路PI3K-Akt通路来促进IR。而chemerin与炎症、IR密切相关,因此chemerin在慢性肾病中可能扮演重要角色。研究[37]发现,肌酐清除率、血清肌酐与血清chemerin密切相关。与健康个体相比,慢性肾脏疾病患者的血清中chemerin水平增高;终末期肾病患者进行肾脏移植后,患者血清中的chemerin恢复正常,也提示chemerin与患者肾功能密切相关[38]。此外,与其结构类似的缓激肽在肾脏中高表达[3]。

6 Chemerin与心血管疾病的关系

Chemerin与心血管疾病密切相关。循环中高chemerin水平是独立于其他心脑血管的危险因素,使冠状动脉疾病风险和增加动脉粥样硬化程度增加[39]。在稳定性心绞痛患者中,斑块数量与chemerin正相关[40]。 Chemerin促进心血管疾病可能与chemerin可改变内皮黏附水平、内皮细胞对脂质和糖的渗透,或调节E选择素和细胞间黏附分子-1((ICAM-1)之间的相互作用等有关[41]。Chemerin还可增加基质金属蛋白酶(MMP)的产生,而体外实验证明MMP在血管重塑和生长中扮演重要角色[42]。此外,颈动脉内膜中层厚度增加是心肌梗死、脑梗死等心血管疾病发生的危险因素。Ali等[43]研究发现,颈动脉内膜中层厚度与chemerin正相关。在一项对中国患者中的研究中,冠心病患者相比健康人群的血清中的chemerin水平更高[44]。Bozaoglu等[17]发现,MS患者chemerin水平较健康人群高,其与血压、三酰甘油、空腹血糖、收缩压等密切相关。Takahashi等[36]也发现,chemerin水平与收缩压、三酰甘油、空腹血糖正相关,与高密度脂蛋白(HDL)负相关。此外,有研究[39]表明,血清chemerin水平与动脉粥样硬化并发症正相关。

7 Chemerin与NAFLD的关系

NAFLD是MS在肝脏的主要表现。不同的脂肪因子可能在脂肪浸润的肝脏炎症和纤维化进展中发挥了至关重要的作用[17,45]。然而,这些脂肪细胞因子及其在NAFLD发病中的作用尚待研究。研究[12]报道,chemerin及其受体在肝脏中高表达,这表明肝脏是脂肪信号的另一个重要目标。Chemerin在肝代谢调控中的潜在机制可能在于其对肝脏天然免疫细胞的直接作用,包括Kupffer细胞和自然杀伤细胞。Asalah等[46]研究表明,在高脂饮食喂养或NAFLD大鼠中,血清chemerin逐渐增加且血清chemerin水平与肝损伤的病理组织学评分正相关。Weigert等[32]表明,肥胖患者全身血清chemerin浓度及脂肪组织增加。Asalah等[46]研究表明,与正常对照组相比,NAFLD和非酒精性脂肪性肝炎(NASH)患者血清chemerin浓度显著增高。此外,Zabel等[47]表明,肝硬化患者肝脏血浆chemerin增高。研究[18]表明,在病态肥胖患者中,chemerin与脂肪肝标志物密切相关,并可在手术减肥后明显降低。

综上所述,chemerin与代谢相关疾病密切相关,其可能为代谢性疾病发生的重要环节。研究chemerin在代谢相关疾病中的病理生理基础,或许可为延缓或治疗代谢相关疾病如2型糖尿病、NAFLD、心血管疾病等提供新靶点。

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