鞘氨醇激酶信號(hào)通路在肝纖維化中的作用機(jī)制

孫 躍， 蘭 天， 郭 姣

(1 廣東藥科大學(xué) a.中醫(yī)藥研究院; b.藥學(xué)院藥理系， 廣州 510006；2 廣東省代謝病中西醫(yī)結(jié)合研究中心， 廣州 510006)

鞘氨醇激酶信號(hào)通路在肝纖維化中的作用機(jī)制

孫 躍1a,2， 蘭 天1a,1b,2， 郭 姣1a,2

(1 廣東藥科大學(xué) a.中醫(yī)藥研究院; b.藥學(xué)院藥理系， 廣州 510006；2 廣東省代謝病中西醫(yī)結(jié)合研究中心， 廣州 510006)

肝纖維化的形成主要體現(xiàn)為肝星狀細(xì)胞的激活和細(xì)胞外基質(zhì)合成降解的失衡。鞘氨醇激酶-1-磷酸鞘氨醇-1-磷酸鞘氨醇受體(SphK-S1P-S1PRs)信號(hào)通路在調(diào)控細(xì)胞的增殖、遷移以及炎癥反應(yīng)等生命活動(dòng)中發(fā)揮重要作用。介紹了SphK、S1P、S1PRs的分布及生物學(xué)功能，簡述了SphK-S1P-S1PRs信號(hào)通路在肝纖維化中的作用機(jī)制及其研究進(jìn)展。多項(xiàng)研究證實(shí)SphK-S1P-S1PRs信號(hào)通路在肝纖維化疾病研究中起關(guān)鍵性作用，深入的探索有助于為臨床上肝纖維化治理和藥物新靶點(diǎn)開發(fā)提供新的思路。

肝硬化； 鞘氨醇激酶； 轉(zhuǎn)化生長因子β1； 信號(hào)傳導(dǎo)； 綜述

肝纖維化是機(jī)體對(duì)各種病因引起的一種慢性肝損傷的疤痕修復(fù)過程，其可能進(jìn)一步發(fā)展成肝硬化甚至肝衰竭并伴有門靜脈血栓[1]。鞘磷脂(sphingomyelin, SM)及其代謝物參與了細(xì)胞的多樣生物學(xué)效應(yīng)，其中鞘氨醇激酶(sphingosine kinase, SphK)是鞘脂類代謝平衡中的一個(gè)關(guān)鍵限速酶，SM代謝物神經(jīng)酰胺(ceramide, Cer)、神經(jīng)鞘氨醇(sphingosine，Sph)和1-磷酸鞘氨醇(sphingosine-1-phosphate, S1P)三者之間的動(dòng)態(tài)平衡決定著細(xì)胞的生存和死亡。S1P的生物學(xué)功能為刺激細(xì)胞生長、抑制細(xì)胞凋亡，Cer和Sph的生物學(xué)功能表現(xiàn)為促進(jìn)細(xì)胞生長停滯和凋亡[2]。研究[3-5]發(fā)現(xiàn)，在一些慢性炎癥反應(yīng)、纖維化、自身免疫性疾病的器官或組織中SphK-S1P-S1PRs(1-磷酸鞘氨醇受體)信號(hào)通路可能出現(xiàn)生物活性的改變從而影響了疾病的進(jìn)程。目前SphK-S1P-S1PRs信號(hào)通路在肝纖維化中的詳細(xì)作用機(jī)制還有待闡明，本文將對(duì)SphK信號(hào)通路在肝纖維化中的作用機(jī)制與進(jìn)展作一綜述。

1 SM及其代謝物的概述

SM作為細(xì)胞膜結(jié)構(gòu)的主要成分之一，維持著生物膜的完整性。在某些外界條件刺激下鞘磷脂酶將SM分解為Cer和磷酸膽堿。Cer在神經(jīng)酰胺酶的作用下裂解成Sph，Cer的次級(jí)代謝產(chǎn)物Sph又在SphK的作用下裂解為S1P。生成的S1P可以被S1P磷酸酶活化參與Cer的合成；或被S1P裂解酶降解后移到甘油酯的生物合成中，也可釋放到細(xì)胞外在血小板或內(nèi)皮細(xì)胞中發(fā)揮作用[6]。細(xì)胞內(nèi)的Cer、Sph和S1P被稱之為“鞘脂-變阻器”，三者通過酶促反應(yīng)維持動(dòng)態(tài)平衡從而決定細(xì)胞正常的生物學(xué)功能[7]。

1.1 SphK的分布及生物學(xué)功能 SphK最初是由Obinata等從大鼠腎臟中純化提取得到的分子量為49 kD的一種脂類激酶。SphK存在SphK1和SphK2兩種亞型，二者在氨基酸序列和組成上雖高度相似，卻在組織分布、細(xì)胞定位、生物學(xué)功能上存在顯著的差異[8]。SphK1在未受刺激的情況下存在于細(xì)胞質(zhì)內(nèi)，主要在肺、肝、脾等器官和組織中表達(dá)，其生物學(xué)功能為促進(jìn)細(xì)胞增長，抑制凋亡。研究[9]表明活化后的SphK1受到G蛋白偶聯(lián)受體、促炎細(xì)胞因子、免疫球蛋白受體等刺激下轉(zhuǎn)移到質(zhì)膜后參與生物學(xué)效應(yīng)。SphK2存在于細(xì)胞核和線粒體內(nèi)，多在肝和心臟中表達(dá)，其生物學(xué)功能表現(xiàn)為促進(jìn)細(xì)胞凋亡并抑制細(xì)胞存活[10]。

1.2 S1P的分布及生物學(xué)功能 S1P是一種具有廣泛生物活性的磷脂酶，由SphK1催化而來，血液中S1P主要來自血小板和紅細(xì)胞。大多數(shù)的血源性S1P與血清蛋白及高密度脂蛋白結(jié)合，僅少數(shù)低濃度的S1P以游離形式存在血液中。S1P通過刺激信號(hào)通路參與了許多病理生理學(xué)反應(yīng)如：細(xì)胞的增殖、分化、遷移、存活、血管生成以及免疫功能的調(diào)節(jié)[11]。研究[12]表明S1P的梯度形成對(duì)于許多生理功能是必須的并具有雙重效應(yīng)。細(xì)胞內(nèi)S1P濃度不僅受到SphK1的調(diào)節(jié)，還與S1P裂解酶、S1P磷酸酶的催化降解相關(guān)。S1P是促纖維化(心臟纖維化、肺纖維化、腎纖維化、肝纖維化等)的關(guān)鍵調(diào)節(jié)劑[13-15]。S1P對(duì)細(xì)胞的遷移與細(xì)胞的類型、S1P濃度及S1PRs表達(dá)模式等多種因素相關(guān)[16]。S1P的作用機(jī)制主要表現(xiàn)為兩方面：(1)作為細(xì)胞外遞質(zhì)通過細(xì)胞膜上的轉(zhuǎn)運(yùn)體移到細(xì)胞外部，同其自身受體S1PRs相結(jié)合間接激活胞內(nèi)信號(hào)的轉(zhuǎn)導(dǎo)，參與一系列生物學(xué)效應(yīng)；(2)作為細(xì)胞內(nèi)轉(zhuǎn)導(dǎo)的“第二信使”直接激活下游信號(hào)從而介導(dǎo)多樣的生物學(xué)效應(yīng)。

1.3 S1PRs的分布及生物學(xué)功能 目前為止S1P的生物學(xué)功能大多涉及S1PRs的活化而引發(fā)一系列細(xì)胞反應(yīng)[如：促進(jìn)細(xì)胞增殖，增加細(xì)胞外基質(zhì)(ECM)產(chǎn)生，刺激黏附連接等]或通過激活不同的信號(hào)通路(如：絲裂原活化蛋白激酶途徑、PI3K/Akt通路和PLC/DAG/PKC通路)誘導(dǎo)細(xì)胞的多樣反應(yīng)[17-18]。S1PRs受體存在5種亞型(S1PR1～5)，其中S1PR1～3在人和小鼠的多種組織中表達(dá)，S1PR4僅表達(dá)在淋巴和造血組織中，S1PR5表達(dá)于中樞神經(jīng)系統(tǒng)。近年來許多研究熱點(diǎn)集中在S1PRs，研究[19]顯示S1PRs在一些免疫細(xì)胞(巨噬細(xì)胞、單核細(xì)胞、T淋巴細(xì)胞、B淋巴細(xì)胞等)和神經(jīng)細(xì)胞(少突膠質(zhì)細(xì)胞、星形膠質(zhì)細(xì)胞、神經(jīng)元細(xì)胞等)中均有部分表達(dá)，它們大多調(diào)節(jié)細(xì)胞的存活、遷移、增殖等。目前的研究[20-22]發(fā)現(xiàn)S1PRs主要在調(diào)節(jié)血管屏障功能、淋巴運(yùn)輸、免疫及癌癥方面起主要作用，其中S1PR1、S1PR2、S1PR3占主導(dǎo)作用。

2 肝纖維化密切相關(guān)的細(xì)胞及細(xì)胞因子

與肝纖維化密切相關(guān)的細(xì)胞主要有：肝星狀細(xì)胞(HSC)、肝竇內(nèi)皮細(xì)胞、Kupffer細(xì)胞等；相關(guān)的細(xì)胞因子有：轉(zhuǎn)化生長因子(TGF)β1、血小板源性生長因子(platelet derived growth factor, PDGF)等。它們?cè)诟卫w維化中起到至關(guān)重要的作用。TGFβ1是生長因子家族成員之一，主要分布在Kupffer細(xì)胞、HSC中。TGFβ1作為一個(gè)經(jīng)典的細(xì)胞因子在肝纖維化中的研究較為深入。它是目前促肝纖維化最強(qiáng)的細(xì)胞因子同時(shí)也被視為調(diào)節(jié)免疫細(xì)胞的抗炎細(xì)胞因子[23]。TGFβ1的主要作用是激活HSC以及促使肌成纖維細(xì)胞產(chǎn)生ECM[24]。TGFβ1的纖維化作用大多是通過TGFβ/Smads信號(hào)轉(zhuǎn)導(dǎo)途徑參與形成的。研究[25-26]表明SphK-S1P-S1PRs與TGFβ1二者之間存在密切的聯(lián)系，TGFβ1作為 SphK1表達(dá)和活性的有效誘導(dǎo)物，通過TGFβ1受體依賴的方式誘導(dǎo)SphK1的激活并上調(diào)SphK1、Ⅰ型膠原蛋白和Ⅲ膠原蛋白的表達(dá)使細(xì)胞內(nèi)的S1P水平增加。PDGF是體外HSC最強(qiáng)的促細(xì)胞分裂因子[27]，可促進(jìn)HSC的增殖并誘導(dǎo)TGFβ1在肝組織中的積累，其分泌產(chǎn)生的放大效應(yīng)使ECM在肝臟內(nèi)大量沉積。Katsuma等[28]在HIGA小鼠中發(fā)現(xiàn)PDGF能促進(jìn)SphK及S1P的高表達(dá)，S1P結(jié)合膜表面受體通過G蛋白途徑進(jìn)而促進(jìn)細(xì)胞的增殖。Katsuma等[29]首次發(fā)現(xiàn)S1P與TGFβ1信號(hào)之間的交叉關(guān)系，一方面S1P刺激腎小球系膜后會(huì)導(dǎo)致結(jié)締組織生長因子的表達(dá)增強(qiáng)，以依賴Smad3的方式發(fā)生；另一方面TGFβ1能顯著上調(diào)SphK1 mRNA和蛋白總量從而造成SphK活性在表皮纖維母細(xì)胞中持續(xù)增長和S1P磷酸酶的活性降低。

3 SphK-S1P-S1PRs在肝纖維化中的作用機(jī)制

SphK-S1P-S1PRs是一條攸關(guān)細(xì)胞生死的信號(hào)通路，在調(diào)節(jié)細(xì)胞凋亡、代謝以及炎癥反應(yīng)等疾病過程起到了至關(guān)重要的作用。研究已經(jīng)證實(shí)SphK-S1P-S1PRs信號(hào)通路參與了腎、肺、腫瘤等疾病的病理過程。一些相關(guān)細(xì)胞或細(xì)胞因子同SphK-S1P-S1PRs信號(hào)通路發(fā)生直接或間接的關(guān)聯(lián)進(jìn)而表現(xiàn)出不同的生物學(xué)效應(yīng)，并在不同的細(xì)胞環(huán)境下介導(dǎo)纖維化。

3.1 S1P與肝纖維化 最新研究[30]表明通過降低淋巴中S1P的濃度梯度和滯留肝臟中的HSC可減輕肝纖維化。FTY720和芬戈莫德是S1P常見的拮抗劑[31]，芬戈莫德可抑制PDGF刺激后的細(xì)胞增殖。FTY720可與S1PRs結(jié)合使其內(nèi)化并阻止下游信號(hào)的應(yīng)答，使肝臟中HSC滯留從而減輕肝纖維化[32]。SM從頭合成的產(chǎn)物棕櫚酸酯可以誘導(dǎo)肝細(xì)胞中S1P的表達(dá)，并通過S1PR3激活HSC。S1P信號(hào)轉(zhuǎn)導(dǎo)受到抑制，與肝臟中促炎單核細(xì)胞衍生的巨噬細(xì)胞減少有關(guān)，進(jìn)而改善小鼠非酒精性脂肪性肝炎[33]。S1P可激活免疫細(xì)胞的趨化性和促炎癥信號(hào)[34]，其促纖維化作用通常涉及兩個(gè)平行的信號(hào)轉(zhuǎn)導(dǎo)途徑即Rho/ROCK和Smad蛋白激活，并由S1PR2和S1PR3激活來觸發(fā)。研究[35]證明S1P刺激肌成纖維細(xì)胞的轉(zhuǎn)化和膠原的產(chǎn)生是依賴于Rho激酶的活化。在 CCl4/膽道結(jié)扎誘導(dǎo)的急慢性肝損傷的小鼠模型中，肝組織和血清的S1P均有增加，同時(shí)出現(xiàn)S1PR3表達(dá)上調(diào)而S1PR1、S1PR2無顯著變化的現(xiàn)象。S1P還通過S1PR1/3誘導(dǎo)Ang1的表達(dá)，來驅(qū)動(dòng)肝纖維化病理性血管的生成[36]。

3.2 SphK與肝纖維化 SphK1在保護(hù)乙醇誘導(dǎo)的肝損傷以及膽汁鹽誘導(dǎo)的凋亡中起主要作用[37-38]。在高飽和脂肪攝食誘導(dǎo)的非酒精脂肪性肝炎小鼠模型中Sphk1介導(dǎo)肝臟炎癥的發(fā)生并在肝細(xì)胞中啟動(dòng)促炎癥信號(hào)轉(zhuǎn)導(dǎo)[39]。同時(shí)還有研究[40]指出SphK-S1P-S1PRs信號(hào)通路參與了肝細(xì)胞生成素對(duì)乙醇誘發(fā)的肝損傷和纖維化的保護(hù)作用。SphK1通過TGFβ1誘導(dǎo)基質(zhì)金屬蛋白酶抑制劑1的轉(zhuǎn)錄調(diào)節(jié)，從而抑制成纖維細(xì)胞中ECM的降解。最近的研究[41]還指出褪黑素能夠減弱大鼠或小鼠引起的多種纖維化途徑，其抑制S1P的產(chǎn)生并降低SphK1、S1PR1、SP1R3和鞘磷脂酶的表達(dá)。

3.3 S1PRs與肝纖維化 研究[42]表明S1P / S1PRs信號(hào)軸調(diào)控HSC的遷移和纖維激活，其中S1PR1、S1PR3表現(xiàn)為正調(diào)控而S1PR2對(duì)細(xì)胞的遷移起到負(fù)調(diào)控的作用。在膽汁淤積的肝損傷小鼠模型中，S1P刺激巨噬細(xì)胞的遷移并誘導(dǎo)形態(tài)的重排，其通過激活S1PR2、S1PR3來擴(kuò)增PI3K和Rac信號(hào)通路，最終促使骨髓來源的單核細(xì)胞/巨噬細(xì)胞的遷移和積聚[35]。S1PR2介導(dǎo)的信號(hào)通路在膽汁酸誘導(dǎo)的血管細(xì)胞增生和膽汁淤積引起的小鼠肝損傷中起到了重要作用[43]。研究[44]發(fā)現(xiàn)S1PR1可通過與高密度脂蛋白結(jié)合的天然配體誘導(dǎo)肝再生并抑制肝纖維化的發(fā)生。最新的研究[45]指出結(jié)合膽汁酸可激活S1PR2，其通過細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)途徑激活核SphK2，增加細(xì)胞核中S1P的水平，從而誘發(fā)膽汁淤積引起的肝損傷。

4 總結(jié)與展望

國內(nèi)外的研究證實(shí)SphK-S1P-S1PRs信號(hào)通路在多個(gè)器官組織中均有表達(dá)。目前肝纖維化的發(fā)生機(jī)制較為復(fù)雜，其主要通過細(xì)胞-細(xì)胞、細(xì)胞-基質(zhì)、基質(zhì)-基質(zhì)三者之間的相互作用最終形成一個(gè)網(wǎng)絡(luò)調(diào)控體系。TGFβ1作為一個(gè)經(jīng)典的細(xì)胞因子在肝纖維化中的研究較為深入，但TGFβ1是否能直接作用于SphK-S1P-S1PRs信號(hào)通路來影響肝纖維化的發(fā)生不得而知。另外S1PR4、S1PR5目前對(duì)于肝纖維化的研究還有待進(jìn)一步探索。因此，現(xiàn)階段需不斷深入研究SphK通路及相關(guān)因子在肝纖維化中的調(diào)控機(jī)制，從而更加有效的預(yù)防肝纖維化的發(fā)生，為臨床上肝纖維化治療和藥物新靶點(diǎn)開發(fā)提供新思路。

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引證本文：SUN Y, LAN T, GUO J. Research advances in the sphingosine kinase signaling pathway in liver fibrosis[J]. J Clin Hepatol, 2017, 33(9): 1798-1801. (in Chinese) 孫躍， 蘭天， 郭姣. 鞘氨醇激酶信號(hào)通路在肝纖維化中的作用機(jī)制[J]. 臨床肝膽病雜志, 2017, 33(9): 1798-1801.

(本文編輯：王 瑩)

Researchadvancesinthesphingosinekinasesignalingpathwayinliverfibrosis

SUNYue,LANTian,GUOJiao.

(InstituteofChineseMedicine,GuangdongPharmaceuticalUniversity,GuangdongMetabolicDiseaseResearchCenterofIntegratedChineseandWesternMedicine,Guangzhou510006,China)

Formation of liver fibrosis mainly involves activation of hepatic stellate cell and imbalance between synthesis and degradation of extracellular matrix. The sphingosine kinase (SphK)/sphingosine 1-phosphate (S1P)/sphingosine 1-phosphate receptors (S1PRs) signaling pathway plays an important role in the regulation of cell life activities including proliferation, migration, and inflammatory response. This article introduces the distribution and biological functions of SphK, S1P, and S1PRs and elaborates on the research advances in mechanism of action of the SphK/S1P/and S1PRs signaling pathway in liver fibrosis. Many studies have confirmed the important role of the SphK/S1P/and S1PRs signaling pathway in liver fibrosis, and in-depth exploration helps to provide new thoughts for clinical treatment of liver fibrosis and development of new drug targets.

liver cirrhosis； sphingosine kinase； transforming growth factor beta1； signal transduction； review

10.3969/j.issn.1001-5256.2017.09.038

2017-04-17；

：2017-05-24。

廣東省科技廳國際合作項(xiàng)目(2015A050502050)；廣東省教育廳創(chuàng)新強(qiáng)校項(xiàng)目(2014GKPT021)

孫躍(1993-)，女，主要從事肝纖維化的基礎(chǔ)研究。

郭姣，電子信箱：gyguoyz@163.com。

R575.2

：A

：1001-5256(2017)09-1798-04