修回日期: 2009-12-02
接受日期: 2009-12-07
在线出版日期: 2010-01-18
肝纤维化是肝脏对各种慢性损伤的一种反应, 以肝脏细胞外基质异常过度沉积为特征. 脂肪细胞因子主要指由脂肪组织分泌的一类多肽分子, 其在慢性肝病如非酒精性脂肪性肝病的发病过程中具有重要作用. 本文就瘦素、脂联素和抵抗素在肝纤维化中的作用作一综述.
引文著录: 袁聪, 郑城婷, 许保, 杨丽. 瘦素、脂联素和抵抗素在肝纤维化中的研究进展. 世界华人消化杂志 2010; 18(2): 149-154
Revised: December 2, 2009
Accepted: December 7, 2009
Published online: January 18, 2010
Liver fibrosis is a wound healing reaction in response to a variety of chronic liver insults and is characterized by excessive extracellular matrix deposition within the liver. The term "adipocytokines]represents a group of polypeptide molecules produced primarily by adipose tissue. Accumulating evidence demonstrates that adipocytokines play a pivotal role in the pathogenesis of chronic liver diseases, such as nonalcoholic fatty liver disease. In this article, we will summarize the recent findings concerning the role of adipocytokines, such as leptin, adiponectin and resistin, in liver fibrogenesis.
- Citation: Yuan C, Zheng CT, Xu B, Yang L. Advances in understanding the role of leptin, adiponectin and resistin in liver fibrogenesis. Shijie Huaren Xiaohua Zazhi 2010; 18(2): 149-154
- URL: https://www.wjgnet.com/1009-3079/full/v18/i2/149.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v18.i2.149
肝纤维化作为慢性肝病的重要阶段, 以过多的细胞外基质(extracellular matrix, ECM)沉积为特征, 其病因包括: 肝炎病毒感染、乙醇、药物、免疫、肥胖等. 与腹型肥胖和胰岛素抵抗关系密切的非酒精性脂肪性肝病(nonalcoholic fatty liver disease, NAFLD)[1,2]现已成为一种常见的慢性肝病, 他包括单纯性脂肪变性(simple steatosis, SS)、非酒精性脂肪性肝炎(nonalcoholic steatohepatitis, NASH)和肝硬化. 其中, NASH以脂肪变性、炎症和纤维化为特征[3]. NAFLD作为代谢综合征在肝脏的表现, 研究表明NAFLD患者的肝脏炎症和纤维化程度与腹部脂肪组织含量密切相关[4]. 不仅如此, 代谢综合征还会增加慢性乙型肝炎患者发生肝硬化的风险[5]. 越来越多的研究表明脂肪组织不仅参与能量代谢, 而且具有活跃的内分泌功能, 能分泌多种脂肪细胞因子, 对外周器官如肝脏产生重要影响[6]. 本文就瘦素(leptin)、脂联素(adiponectin)和抵抗素(resistin)在肝纤维化中的作用进行综述.
脂肪组织有白色脂肪组织(white adipose tissue, WAT)和褐色脂肪组织(brown adipose tissue, BAT)之分. BAT主要见于新生儿. WAT由脂肪细胞、前脂肪细胞、巨噬细胞、内皮细胞和白细胞等组成. 在成人, WAT主要有三大功能: (1)贮存能量; (2)水解甘油三酯, 提供游离脂肪酸, 为组织提供能量; (3)分泌细胞因子, 如瘦素、脂联素、内脂素、apelin、vaspin、hepcidine、chemerin、omentin等, 统称为脂肪细胞因子(adipocytokines)[6,7]. 有些脂肪细胞因子主要由脂肪细胞分泌, 有些则由基质细胞成分如巨噬细胞、成纤维细胞和单核细胞等产生[7]. 这些细胞因子通过自分泌、旁分泌、内分泌等形式, 发挥广泛的生物学效应, 如能量平衡、前脂肪细胞的分化、胰岛素敏感性、炎症和纤维化等[6,8]. 不同部位如血管周围和心脏周围等的脂肪组织可能在不同的疾病中发挥着各自的调节作用, 而腹部脂肪组织的分泌产物可通过门静脉直接到达肝脏, 在肝脏疾病中发挥重要作用[7].
瘦素是由Zhang等[9]在1994年利用定位克隆(positional cloning)技术发现的一种肽类激素, 由肥胖基因(ob)编码. 人ob基因位于7号染色体的长臂(7q31.3), 由3个外显子和2个内含子构成. 瘦素是一种分泌蛋白, 由167个氨基酸组成, 相对分子质量为16 kDa. 瘦素必须与相应受体(ob-R)结合才能发挥作用. 目前发现ob-R有a、b、c、d、e和f 6种亚型[10], 其中ob-Rb为长型受体, 也是功能性受体, 通过激活JAK2/STAT3通路介导瘦素的大多数生物学效应; ob-Re是可溶性受体, 与循环中的瘦素形成复合物, 通过调节游离与结合的瘦素比例可改变其生物学活性[11]; 其余为短型受体. 早期的研究发现, 瘦素通过作用于中枢神经系统对食欲和脂肪含量起重要的调节作用. 动物实验发现, 瘦素具有促肝纤维化效应. Ikejima等[12]发现, 在四氯化碳(CCl4)和硫代乙酰胺(thioacetamide, TAA)诱导的C57BL/6 ♂小鼠急、慢性肝损伤模型中, 注射外源性瘦素能进一步增强肝脏转化生长因子(transforming growth factor, TGF)-β1和Ⅰ型前胶原的表达. Honda等[13]应用先天缺乏瘦素的ob基因敲除(ob/ob)小鼠为动物模型, 发现TAA几乎不能诱导其肝纤维化的发生以及Ⅰ型前胶原的表达. Leclercq等[14]研究也发现, 经高脂饲料喂养或进行CCl4诱导肝损伤, ob/ob小鼠并没有出现肝纤维化, 也未检测到Ⅰ型胶原表达上调; 但给小鼠补充外源性瘦素使其恢复至生理水平后, ob/ob小鼠则发生了肝纤维化. 在瘦素受体敲除(fa/fa)Zucker大鼠模型中, TAA也几乎不能诱导肝纤维化的发生[15]. Zucker大鼠经胆管结扎术(bile duct ligation, BDL)后, 同样未引起肝纤维化[16]. 在TAA诱导的小鼠肝纤维化模型中, 瘦素拮抗剂竞争性抑制瘦素的作用后, 肝纤维化程度得到明显改善[17]. 这表明无论是代谢性、肝后性还是中毒性慢性肝损伤, 瘦素都是肝纤维化发生的重要因素. 另外, 给予胆碱-蛋氨酸缺乏(methionine and choline deficient, MCD)饲料喂养后, 瘦素受体敲除(db/db)小鼠则能发生与野生型相当或更明显的肝纤维化[18]. 此型小鼠只表达瘦素短型受体, 提示短型受体也能充分介导瘦素的促纤维化效应.
鉴于肝星状细胞(hepatic stellate cell, HSC)作为肝纤维化时细胞外基质的主要来源细胞, 许多学者进行了大量研究以探讨瘦素发挥促纤维化效应的细胞及分子机制. 目前, 一种观点认为瘦素直接作用于HSC并激活下游信号途径导致ECM沉积; 另一种观点则认为, 由于枯否细胞(kupffer cell, KC)及窦内皮细胞(sinusoidal endothelial cell, SEC)存在功能性瘦素受体, 瘦素刺激这些细胞释放促纤维化因子如TGF-β1, 后者再激活HSC[19]. Saxena等[20]发现, 正常大鼠HSC及其细胞株(T6)均表达ob-Rb, 此功能性受体在静息的HSC呈低表达, 而在活化后表达增强. 在外源性瘦素刺激下, HSC的Ⅰ前胶原基因表达及STAT3磷酸化增加. 在人肝星状细胞株LX-2中, Cao等[21-23]先后发现瘦素能诱导其表达TIMP-1和I型胶原, 并抑制MMP-1的表达; 瘦素还能调节CTGF的表达[24]. Elinav等[17]也发现原代大鼠HSC表达ob-Rb, 瘦素可直接诱导HSC表达Ⅰ型胶原和α-平滑肌肌动蛋白(α-smooth muscle actin, α-SMA). 这些研究均提示瘦素对HSC存在直接效应. 然而, Ikejima等[15]却发现HSC表达的是非功能性ob-Ra, 并不是ob-Rb, 瘦素不能促进HSC的STAT3磷酸化与Ⅰ型前胶原基因表达. 他们发现KC及SEC存在功能性ob-Rb, 瘦素刺激其高表达TGF-β1, 后者诱导HSC表达促纤维化因子. Ding等[16]报道, 激活的HSC可分泌大量的瘦素. 因此, 推测瘦素可能通过与周围细胞的相互作用发挥其效应, HSC可能是肝内瘦素的细胞来源之一, 而不是瘦素作用的直接效应细胞. 最近的研究的确表明, 体外培养的原代HSC不能直接被瘦素激活, 而是由KC介导实现的. Wang等[19]将体外培养的大鼠HSC与瘦素孵育后, 发现除了能引起HSC增殖和Ⅰ型胶原表达外, HSC的α-SMA表达并不上调, 但是用瘦素刺激KC后的条件培养基培养HSC, 就能显著上调Ⅰ型胶原、TIMP-1、TGF-β1、CTGF以及α-SMA的表达. 然而, 用瘦素处理的SEC条件培养基却不能上调这些促纤维化因子的表达, 也不能激活HSC. 另外, 瘦素能直接作用于KC, 上调CTGF的表达[19]. 瘦素也能促进HSC表达去甲肾上腺素, 并激活血管紧张素系统导致肝纤维化[25]. 目前, 瘦素的促纤维化作用机制仍未完全阐明, 已有的实验结果也存在诸多差异, 尚有待进一步的研究以探讨多个细胞之间的相互作用. 瘦素还具有促炎症效应. 通过NF-κB介导上调单核细胞趋化蛋白(monocyte chemotactic protein, MCP)-1, 后者可进一步使单核细胞和活化的T淋巴细胞聚集, 增强肝脏损伤的炎症反应[26]. 瘦素也能促进血管生成, 他可刺激HSC表达血管内皮生长因子(vascular endothelial growth factor, VEGF)[26]. 许多临床研究探讨了血清瘦素水平与肝纤维化、肝硬化的相关性. Bolukbas等[27]检测了乙型肝炎和丙型肝炎后肝硬化与正常对照组的血清瘦素水平, 发现肝硬化者其水平明显升高. 另外酒精性肝硬化患者血清瘦素水平也升高[28]. 然而, 有关NAFLD患者血清瘦素水平的报道结果却不尽一致. Uygun等[29]报道, 与1级NASH患者相比, 2级和3级患者有更高的血清瘦素水平. Chitturi等[30]也在NASH患者中检测到高水平的血清瘦素, 但他们发现瘦素水平与肝脏脂肪变性直接相关, 而不是肝脏炎症和纤维化严重程度的独立预测因子. 也有研究发现NASH患者与单纯脂肪肝患者血清瘦素水平没有区别[31]. 这些研究结果的差异, 提示血清瘦素水平尚不能作为肝纤维化的血清学指标.
脂联素是由apM1基因编码的蛋白质, 含244个氨基酸残基, 该基因定位于3q27. 此蛋白质主要由脂肪细胞分泌, 有低分子质量(low molecular weight, LMW)、中分子质量(medium molecular weight, MMW)和高分子质量(high molecular weight, HMW)多聚体3种形式存在[32]. 脂联素主要有AdipoR1和AdipoR2两种受体. AdipoR1广泛分布于多种组织和器官, 主要表达于骨骼肌, AdipoR2主要存在于肝脏. 另外, T-钙黏蛋白(T-cadherin)也是脂联素受体[33]. 脂联素与其受体结合后, 发挥多种重要的生物学作用, 参与血脂血糖代谢、炎症等病理生理过程, 增强胰岛素敏感性以及抗高血糖和抗动脉粥样硬化等[34]. 已有的研究表明, 脂联素具有保护肝脏和抗肝纤维化作用. 在动物模型中, 无论是酒精性肝病小鼠还是NAFLD小鼠, 血清中的脂联素水平均明显下降[35]. 补充外源性脂联素后, 肝脏肿大和脂肪变性明显改善, 肝脏炎症缓解, 血清ALT水平下降. 这些效应是脂联素通过诱导脂肪酸氧化、抑制脂肪酸合成、降低肝脏TNF-α表达以及拮抗TNF-α的效应实现的[35]. Kamada等[36]发现, 与野生型小鼠相比, 脂联素基因敲除小鼠在CCl4诱导下出现更明显的肝纤维化, TGF-β1和CTGF表达增强. 如果在CCl4处理前或处理过程中注射腺病毒载体, 过表达脂联素则能预防或减轻野生型小鼠肝纤维化的发生. 在MCD饲料喂养的C57BL/6小鼠NASH模型中, 通过腺病毒载体抑制肝脏AdipoR2的表达水平后, 肝脏脂肪变性、炎症和纤维化加重; 而过表达肝脏AdipoR2水平后, 上述病理改变得到明显缓解[37]. 提示脂联素和肝脏AdipoR2信号途径在NASH的发生过程中发挥重要的保护作用. 细胞实验发现[16,38], HSC表达脂联素受体, 脂联素通过这些受体发挥抗纤维化效应. 脂联素抑制血小板源生长因子(platelet derived growth factor, PDGF)-BB引起的HSC增殖和迁移; 通过抑制Smad2核转位, 减弱TGF-β1引起的促纤维化基因的表达[36]. Ding等[16]发现, 静息的HSC大量分泌脂联素, 而活化后其分泌受到明显抑制; 激活的HSC经质粒转染后, 脂联素能显著减弱HSC的增殖和α-SMA的表达. 临床数据表明, 在慢性肝病的不同阶段, 血清脂联素水平出现相应的变化. Aygun等[39]发现, 在伴有肝脏酶学升高的NAFLD患者中, 血清脂联素水平降低; 随着NASH患者肝脏炎症程度的加重其血清水平进一步降低. Musso等[40]也检测到NASH患者的血清脂联素水平较正常人群明显降低. 然而, Sohara等[41]检测了38例(酒精性1例、乙型肝炎3例、丙型肝炎31例和不明原因3例)肝硬化患者的血清脂联素水平后, 发现肝硬化者较正常人群明显升高, 升高的程度随着肝硬化(Child-Pugh分级)的加重而增加. Hui等[42]发现, 与慢性乙型肝炎后肝纤维化者相比, 出现肝硬化的患者有更高的血清脂联素水平, 而且血清脂联素水平与纤维化程度呈正相关. 他们还发现肝硬化者血清中MMW脂联素水平选择性升高. 鉴于不同分子质量脂联素对不同的受体亲和力不同, 下游信号通路也存在差别, 推测肝硬化可能与HMW和MMW脂联素比例失衡有关[42]. Sohara等[41]认为肝硬化者血清脂联素水平的升高是脂肪细胞生成和肝脏代谢失衡引起的. Tacke等[43]也检测到慢性肝病患者血清脂联素升高, 结合BDL小鼠模型血清脂联素水平升高, 证实经胆道排泄是脂联素清除的途径之一. 推测肝硬化者胆汁分泌障碍可能是导致血清脂联素水平升高的原因之一. 林家煜等[44]认为肝硬化者存在脂联素抵抗, 这可能也是导致其血清水平升高的原因. 也有学者检测了脂联素及其受体在肝脏的表达情况. Kaser等[45]发现无论是mRNA水平还是蛋白水平, 与SS患者相比, NASH患者的肝脏脂联素和AdipoR2表达均降低. NASH患者AdipoR2的mRNA表达水平与肝纤维化程度呈负相关. 他们还发现脂联素主要分布于内皮细胞, AdipoR2主要位于肝细胞, 提示脂联素可能通过旁分泌途径参与NASH的发病过程. Ma等[46]也发现NASH患者的肝脏脂联素表达水平较SS患者下降; 脂联素与肝脏炎症和纤维化程度呈负相关. 然而, Hui等[42]在肝纤维化和肝硬化患者的肝脏组织中均未检测到脂联素mRNA的表达, 但用免疫组织化学方法发现在肝硬化者中脂联素蛋白表达比肝纤维化者增强. 他们认为这是肝脏从循环中摄取脂联素的结果.
抵抗素是2001年由Steppan等[47]发现的一种脂肪细胞因子. 人抵抗素基因定位于19p13.3, 其蛋白质由108个氨基酸组成, 相对分子质量为12.5 kDa. 此因子主要由脂肪细胞分泌, 具有对抗胰岛素作用, 影响葡萄糖代谢和脂代谢[48]. Szalowska等[49]发现无论是在mRNA水平还是蛋白水平, 抵抗素在肝脏的表达均高于脂肪组织. 提示抵抗素的表达也并不仅限于脂肪组织. 在动物模型中, 无论是ob/ob小鼠、db/db小鼠还是高脂饲料喂养的肥胖小鼠模型中, 血清抵抗素水平都升高[47]. 胰岛素增敏剂罗格列酮可降低肥胖小鼠的抵抗素水平[47]. NAFLD患者血清抵抗素水平升高, 抵抗素浓度直接与NASH的炎症程度呈正相关[50]. 与健康人群相比, 肝硬化者的血清抵抗素水平明显升高[51], 并且随着肝硬化程度加重(Child-Pugh分级)而逐渐增加[52]. Tiftikci等[53]报道, 慢性丙型肝炎患者的血清抵抗素水平较正常者明显升高, 但随着肝纤维化程度的加重, 其血清水平却逐渐降低, 二者呈负相关. 在正常人肝脏组织, 抵抗素呈低表达, 而在慢性丙型肝炎和酒精性肝炎患者表达增强; NASH患者的肝脏抵抗素表达增强没有前两者明显[54]. 在酒精性肝炎患者, 肝脏抵抗素的表达水平与肝脏炎症和纤维化程度相关. 抵抗素可直接作用于HSC发挥促炎症效应, 通过激活核因子NF-κB增强MCP-1和IL-8的表达[54]. 目前, 有关抵抗素与慢性肝病的报道有限, 尚需要更多的研究以探讨抵抗素在肝纤维化中的作用.
大量的基础研究和临床试验均发现脂肪细胞因子与慢性肝病如NAFLD关系密切. 肝纤维化作为慢性肝病的重要阶段, 如果致病因素持续存在则可导致终末期肝病. 随着研究的不断深入, 越来越多的脂肪细胞因子被发现参与肝纤维化的发生, 但其作用机制尚需要进一步阐明. 有效的干预和调节脂肪细胞因子的表达模式及其信号通路, 可能为慢性肝病的治疗提供新的途径.
NAFLD包括单纯性脂肪变性(SS)、非酒精性脂肪肝炎(NASH)和肝硬化, 其发病机制复杂. 其中脂肪细胞因子在其发病过程中具有重要作用. 研究脂肪细胞因子在肝纤维化中的作用机制将为NAFLD的诊断和治疗提供新的方向.
陈洪, 副教授, 东南大学附属中大医院消化科
随着研究的不断深入, 越来越多的脂肪细胞因子被发现参与肝纤维化的发生, 但其作用机制尚需要进一步阐明. 而瘦素、脂联素和抵抗素在肝纤维化中的作用机制研究成为热点之一.
Ikejima等发现, 在四氯化碳(CCl4)和硫代乙酰胺(thioacetamide, TAA)诱导的C57BL/6 ♂小鼠急、慢性肝损伤模型中, 注射外源性瘦素能进一步增强肝脏转化生长因子(TGF)-β1和Ⅰ型前胶原的表达. Szalowska等发现无论是在mRNA水平还是蛋白水平, 抵抗素在肝脏的表达均高于脂肪组织.
本文提示, 有效的干预和调节脂肪细胞因子的表达模式及其信号通路, 可能为慢性肝病的治疗提供新的途径.
本文综述了脂肪细胞因子瘦素、脂联素和抵抗素在肝纤维化中作用的研究进展, 内容丰富、新颖, 有一定的参考价值.
编辑:李军亮 电编:吴鹏朕
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