脂联素在非酒精性脂肪性肝病发病机制及诊治中的研究进展

宋 琪，谭诗云

武汉大学人民医院消化内科，湖北 武汉 430060

非酒精性脂肪性肝病(non-alcoholic fatty liver disease，NAFLD)是排除了酒精和其他明确因素而导致的，病理学上以弥漫性肝细胞脂肪变为特征的临床综合征，根据病变程度及发生纤维化与否，NAFLD又可分为单纯性脂肪肝(NAFL)、非酒精性脂肪性肝炎(NASH)及NASH相关性肝硬化[1]。近年来， NAFLD逐渐成为人类最常见的肝脏疾病，该病在全球范围内的发病率为20%～30%[2]，对人类的生命健康造成了极大的威胁。NAFLD是一种多因素引起的疾病，其发病机制尚未完全明确，但脂联素在NAFLD的发病机制中的作用已逐渐得到广泛的认同。本文就脂联素在NAFLD的发病机制及其诊治方面的研究进展作一概述。

1 脂联素及其受体

脂联素最早由SCHERER等[3]在小鼠脂肪细胞中发现，其结构与补体C1q类似，因此又被称为脂肪细胞补体相关蛋白30(Aprc30)，脂联素由244个氨基酸组成，分为球状域、胶原域、可变域和氨基末端信号序列4个区域，其中球状域为其生物活性的关键部位。脂联素是由脂肪细胞分泌的一种具有多种生物学功能的细胞因子，脂联素通过与其受体结合对机体糖脂代谢、胰岛素抵抗、炎症反应、氧化应激等发挥重要的调节作用，脂联素与动脉粥样硬化、糖尿病、肝肾疾病等各种代谢性疾病关系密切，成为这些疾病研究和治疗的新靶点[4]。人体内有生物活性的脂联素受体主要有Adipo R1和Adipo R2，Adipo R1主要分布于骨骼肌，激活腺苷酸活化蛋白激酶(AMPK)，可减少糖异生，促进脂肪酸氧化；Adipo R2主要分布于肝脏，可激活过氧化物酶体增殖物激活受体α(PPAR-α)，可抑制脂质沉积、氧化应激及炎症反应等[5-6]。脂联素通过其受体发挥生物学效应，Adipo R1和Adipo R2基因敲除的小鼠会出现脂质代谢、炎症及氧化应激等多种功能紊乱[6]。

2 脂联素与NAFLD的“二次打击”

多年来，NAFLD的发病机制尚未完全明确，但已证实其发生、发展与胰岛素抵抗、肝脏内脂质沉积、游离自由基大量生成、脂肪组织及肝脏组织的炎症反应有关[7]。目前广为接受的是由DONATI等[8]和DIEHL[9]提出的“二次打击”学说，其中，“初次打击”与肝脂质代谢紊乱及胰岛素抵抗密切相关，“二次打击”与肝脏炎症坏死及氧化应激密切相关。脂联素具有调节脂质代谢、改善胰岛素抵抗、调节炎症反应、抗氧化应激、抗纤维化等一系列生物活性作用，对预防或延缓NAFLD的发生、发展具有显著效果。

2.1脂联素与NAFLD的“初次打击” NAFLD的初次打击主要是脂质过度聚集在肝脏实质细胞内，这一过程与胰岛素抵抗有关，脂联素可改善肝脏脂质代谢紊乱及胰岛素抵抗，抑制肝脏脂肪合成，促进脂肪酸代谢，降低循环中游离脂肪酸浓度，降低肝脏摄取FFA、降低肝细胞内甘油三酯合成并促进其排出，从而抑制脂肪在肝内的沉积。在体外HepG2细胞模型中，脂联素受体—转基因Adipo R1可通过激活AKT信号通路增强脂肪酸细胞代谢，提高细胞生存率[10]。KAMADA等[11]研究表明，脂联素基因敲除的小鼠比野生型小鼠出现肝脏脂肪变性的程度更严重，表明脂联素可降低肝内脂肪沉积。脂联素可通过结合脂联素受体，激活AMPK及PPAR-α等途径改善胰岛素抵抗[12]。上调胰岛素及其受体的表达可通过AMPK通路减少脂质在肝及脂肪细胞内的沉积并改善胰岛素抵抗[13]。WU等[14]研究也提示，黄连素可通过提高脂联素受体表达及脂联素中高分子质量(high molecular weight，HMW)六聚体的比例改善胰岛素抵抗能力。

2.2脂联素与NAFLD的“二次打击” NAFLD的“二次打击”是由各种原因所致的肝细胞内反应性氧产物(reactive oxygen species，ROS)生成增多，超过了肝细胞抗氧化系统清除能力导致氧化应激，氧化应激进一步使脂质产生过氧化损伤，炎症因子释放增多导致肝细胞发生炎症、坏死及纤维化。脂联素可通过改善肝脏氧化应激及炎症、纤维化反应抑制NAFLD的进展。PENG等[15]实验证实，高脂饮食喂养的小鼠出现脂肪性肝炎与脂联素及其受体Adipo R2下调有关。高脂饮食诱导的NASH大鼠NADPH氧化酶复合体及炎症相关基因表达水平升高，而脂联素受体Adipo R2及其基因表达水平降低，表明Adipo R2引起的肝脏炎症和氧化应激可能导致了NASH的进展[16]。高不饱和脂肪酸饮食喂养小鼠的脂联素降低可诱导NASH，这与肝线粒体功能障碍有关[17]，而线粒体正是氧化应激发生的场所。CHENG等[18]通过用脂联素干预氧化应激的细胞证实脂联素可通过激活AMPK通路下调TGF-β1和COL-1水平降低细胞的氧化应激水平。

在NAFLD后期，NAFL可进一步发展形成肝纤维化，脂联素具有抗纤维化的作用，是NAFLD肝纤维化的保护因子。用四氯化碳诱导脂联素基因敲除的小鼠，肝纤维化可通过腺病毒介导脂联素过表达减轻[19]，肝脏星状细胞(HSC)是肝纤维化发生、发展的关键，脂联素可抑制转化生长因子-β1促进纤维化因子表达及HSC的增殖和迁移[19-20]，DONG等[21]研究也表明，脂联素可通过促进HSC释放NO改善肝纤维化。

3 脂联素在NAFLD的诊断及治疗中的作用

3.1脂联素与NAFLD的诊断脂联素是主要由脂肪细胞分泌的蛋白质，脂联素在血清中有低分子质量三聚体、中分子质量六聚体、HMW六聚体三种形式存在，其中HMW的生物活性最强，对肥胖、胰岛素抵抗及糖尿病等代谢综合征有明显的改善作用[22-23]。由于脂联素对各种代谢综合征具有保护作用，许多研究组针对血清脂联素水平对代谢性疾病在临床中诊断疾病的意义进行了研究：HIROSE等[24]研究表明，血清HMW水平与胰岛素抵抗和代谢综合征密切相关，通过改善生活方式降低体质量指数(BMI)的同时可使血清HMW升高，而先天HMW低下者患心血管疾病的可能性更大，这些均提示脂联素对代谢综合征相关疾病有诊断和治疗价值； KISHIDA等[4]证实，血清脂联素含量与人体脂肪含量尤其是内脏脂肪含量呈反比，而体脂量与NAFLD发生也有显著相关性[25]，低脂联素血症与肥胖相关疾病如糖尿病、冠心病、NAFLD等密切相关。

NAFLD作为典型的代谢综合征中的一种，其发病机制与脂联素密切相关，更加提示了血清脂联素水平的降低对NAFLD的发生可能具有一定的提示作用。POLYZOS等[26]研究表明，NAFL及NASH患者血清脂联素水平低于正常对照者，且NASH患者血清脂联素水平比NAFL更低，表明脂联素降低对NAFLD的诊断有一定的指导作用，且脂联素降低水平与NAFLD患者病情严重程度相关。SALMAN等[27]研究表明，NAFL患者血清脂联素水平低于正常对照者，而NASH患者血清脂联素水平及肝脏脂联素受体表达水平均低于NAFL患者，提示脂联素与NAFLD的发生、发展均相关。KOMSHILOVA等[28]通过检测NAFLD患者血清脂联素水平及NAFLD进展情况证实，NAFLD患者血清脂联素水平明显降低，且患者NAFLD病情越重，血清脂联素水平越低。CHERNYAK等[29]研究提出，血清脂联素水平是肥胖患者NAFLD的预测指标。这些研究证实，血清脂联素水平降低对NAFLD的预测、发生、发展均有一定的诊断价值，目前诊断NAFLD的“金标准”仍是活组织检查，其创伤性是它的一大缺点，脂联素可作为潜在的NAFLD诊断及病情严重程度判断指标，为NAFLD的无创性诊断提供一条新的途径。

此外，也有研究者选择将血清脂联素水平与瘦素、饥饿素等其他脂肪因子水平结合起来诊断NAFLD，取得了较好的效果。MACHADO等[30]研究表明，脂联素、瘦素及饥饿素水平异常程度与NAFLD病变程度相关，结合这三种指标的改变对NASH有较准确的诊断作用。低水平脂联素及高水平瘦素均为NAFLD的独立预测指标，而脂联素与瘦素之比更能预测NAFLD，但NAFLD患者早期纤维化水平与脂联素及瘦素水平无相关性[31]，KOEHLER等[32]研究也证实了这一点。

也有文献报道血清脂联素水平与NAFLD无线性关系[33]，该报道指出，血清脂联素水平可预测非肥胖人群NAFLD患病情况，但对BMI高的肥胖人群，是否患NAFLD与血清脂联素水平无相关性，且认为当NAFLD进展至肝硬化阶段时，脂联素与NAFLD病变程度无相关性。提示我们在将血清脂联素水平作为NAFLD诊断指标时，需结合患者BMI水平及NAFLD病程，对BMI较高或进展至肝硬化阶段患者诊断价值有限。

3.2脂联素与NAFLD的治疗由于脂联素所具有的肝保护效应，NAFLD的发生往往与血清脂联素过低有关，上调脂联素的表达水平或激活脂联素受体通道成为治疗NAFLD的一种新思路。SERRANO等[34]研究表明，脂联素启动子激活剂NP-1可降低高脂饮食动物体质量并减轻NAFL病变程度，指出脂联素对NAFLD具有潜在的治疗作用。大豆胚芽可通过上调脂联素激活的AMPK通道表达预防NAFLD[35]。LI等[36]证实，山楂叶总黄酮可通过增强脂联素AMPK信号通路的表达减轻NAFLD小鼠的肝细胞脂肪变程度。球状脂联素可通过改善胰岛素抵抗和肝脂肪变、调节糖脂代谢和胰岛素受体表达对NAFLD起到一定的治疗作用[37]。这些研究均证实了脂联素在治疗NAFLD上能够起到一定的积极性作用，因此，脂联素及其受体激动剂的研发有望成为今后治疗NAFLD的一种新方法。

4 展望

NAFLD作为一种多因素引起的代谢性疾病，其发病机制十分复杂，近年来对其与脂联素之间的研究越来越多，也更加证实了脂联素在NAFLD发病机制中的重要性，同时，脂联素作为潜在的治疗和诊断NAFLD的细胞因子之一，其具体作用机制的研究尚需深入，而这些问题的解决对NAFLD的无创性诊断及治疗都开辟一条新的途径。

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