重视瘦素在肝纤维化领域中的研究

摘要

瘦素(leptin)是一种由肥胖基因编码的分泌型蛋白质, 具有广泛的生物学效应. 近年来的研究显示, 瘦素与肝纤维化形成之间有密切联系. 在慢性病毒性肝炎、酒精性肝硬化、原发性胆汁性肝硬化等患者中均可见血清瘦素水平异常. 目前国内外研究主要集中于瘦素与活化肝星状细胞(HSC)间的关系、瘦素对细胞因子分泌的调控, 以及瘦素对肝纤维化胶原产生及降解的影响. 本文从流行病学入手, 阐述瘦素促进肝纤维化形成的证据, 以探讨瘦素参与肝纤维化的作用机制, 强调瘦素在该领域中的研究已初见端倪, 必须引起我们足够的重视.

关键词: 瘦素; 肝纤维化

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Correspondence to: N/A

Received: March 31, 2005
Revised: April 4, 2005
Accepted: April 9, 2005
Published online: August 15, 2005

Abstract

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Key Words: N/A

0 引言

瘦素(leptin)的命名源于希腊文"leptos", 是指肥胖(obese, ob)基因编码的分泌性蛋白质, 由167个氨基酸组成[1]. 自1994年Zhang et al[2]首次成功定位克隆小鼠ob基因及人类同源序列以来, 对瘦素的研究已由单纯的食欲控制和能量消耗[3-4], 扩展到包括免疫应答、胰岛素分泌、血管内皮发生和损伤愈合等全身各个病理生理过程[5-13]. 最近, 一系列临床及基础研究还显示瘦素可能参与肝纤维化形成, 相关机制的研究正逐步展开.

1 流行病学资料

有统计资料显示: 肥胖人群肝硬化发病率是普通人群的6倍, 而且肥胖是多种慢性肝病(如丙型肝炎、酒精性肝病、非酒精性脂肪性肝病等)肝纤维化发展的重要危险因子[14-23], 提示作为肥胖调控蛋-瘦素, 可能与肝纤维化形成存在某种必然联系.

目前, 有关临床流行病学资料有以下一些特点: (1)慢性肝病患者血清瘦素水平明显异常; (2)血清瘦素水平与慢性肝病的严重程度有关. 但是, 可能受到所选人群、肝病病因及严重程度、机体脂肪含量评估方法等因素影响, 上述特点各家报道结论相佐.

2 瘦素促进肝纤维化形成的直接证据

2001年, Ikejima et al[24]首次证实瘦素在肝纤维化形成中起促进作用. 他们发现在四氯化碳(carbon tetrachloride, CCl₄)或硫代乙酰胺(thioacetamide, TAA)诱导的C57Bl/6雄性小鼠急、慢性肝损伤模型中, 一定浓度外源性瘦素能明显上调a1(Ⅰ)前胶原基因表达, 促进促纤维化因-转化生长因子-b1(transforming growth factor-b1, TGF-b1)以及肝星状细胞(hepatic stellate cell, HSC)活化标志-a-平滑肌肌动蛋白(a-smooth muscle actin, a-SMA)表达.

此后, 多个研究小组先后观察到在瘦素先天缺乏的ob/ob小鼠中, 由CCl₄、TAA或曼氏血吸虫诱导的肝组织纤维化反应明显低于野生型小鼠, 肝组织中的a1(Ⅰ)前胶原、TGF-b1基因表达明显受到抑制; 给予ob/ob小鼠注射外源性瘦素使其回复生理水平, 则肝组织纤维化程度与野生型小鼠相当[25-27], 有力地印证瘦素是肝纤维化发生发展的促进因子.

3 作用机制探讨

瘦素的生物学效应是由瘦素受体(leptin receptor, ob-R)介导的. ob-R为单跨膜细胞表面受体, 目前已发现的有全长型(ob-Rb)及不同剪接(ob-Ra、c、d、f、e)等至少6种形式, 其中ob-Rb是主要的功能性受体. 瘦素与靶细胞表面ob-Rb结合后, 通过激活Janus激酶/信号转导与转录激活因子(janus kinase/signal transducer and activator of transcription, JAK/STAT)途径调控靶基因转录, 也可经分裂素活化蛋白激酶(mitogen-activated protein kinase, MAPK)和磷酸肌醇3激酶(phosphatidylinositol 3-kinase, PI3-K)等通路传递信号[28-37].

早期研究显示活化的HSC能表达瘦素, 然而在HSC仅作为瘦素的来源抑或是瘦素自分泌/旁分泌直接效应细胞这一问题上仍存在分歧. Ikejima et al[38-39]在进行瘦素促肝纤维化作用机制及相关细胞学基础研究时发现:HSC表达的是ob-Ra, 非功能性ob-Rb; 外源性瘦素(100 nmol/L)不能促进HSC的STAT3磷酸化与a1(Ⅰ)前胶原基因表达; 从Zucker大鼠(fa/fa大鼠, 因ob-R基因突变而对瘦素抵抗)和正常大鼠分离的HSC在体外以相同的方式活化, 结合肝窦内皮细胞(sinusoidal endothelial cell, SEC)、库普弗细胞(Kupffer cell, KC)表面均表达ob-Rb, 对外源性瘦素表现为以TGF-b1高表达为特点的应答反应, 推测HSC是瘦素的来源而不是直接效应细胞. 然而, Saxena et al[40-41]认为鉴于正常大鼠HSC及其细胞株均能表达ob-Rb; 在外源性瘦素刺激下, HSC的a2(Ⅰ)前胶原基因及STAT3磷酸化增加; 在JAK2阻滞剂AG490阻断ob-Rb磷酸化后, 瘦素诱导的HSC增殖受到抑制, 提示瘦素直接作用于HSC促进肝纤维化发生.

HSC活化受细胞信号网络系统的调控, 其中TGF-b1起关键性作用. Tang et al[42-43]发现: 外源性瘦素(100 nM)能促进人HSC细胞株表达TGF-b1Ⅱ型受体; 与TGF-b1同时作用于细胞株时, 将使TGF-b1促胶原合成的效应放大至单独作用时的3.5倍, 显示瘦素致肝纤维化机制与TGF-b1密切相关, 二者具有协同作用.

总之, 瘦素与肝纤维化的研究已初见端倪, 必须引起我们重视. 但是, 由于国内外的研究尚处于起步阶段, 要解答"瘦素在肝纤维化形成中的作用到底有多大", 有赖于对其作用机制进行深入研究. 我们认为今后的研究方向有两个方面: (1)开展大规模、多病因、多层次的流行病学调查, 在设计时应摒弃性别、体重、肥胖、糖尿病、肾功能不全等混杂因子的干扰; (2)开展瘦素与细胞信号网络系统的基础研究, 在研究中可采用基因敲除、小RNA干扰等技术控制相互间的影响. 因此, 探明瘦素与肝纤维化的确切关系, 有望揭示肝纤维化机制新的切入点, 对肝纤维化防治具有重要的临床和理论价值.

备注

编辑:张海宁

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