湯志全，石麗，熊晶

綜 述

溶質(zhì)載體SLC家族在非酒精性脂肪性肝病中的研究進(jìn)展

湯志全，石麗，熊晶

中國藥科大學(xué)藥學(xué)院，南京 210009

非酒精性脂肪肝病(non-alcoholic fatty liver disease，NAFLD)與肥胖癥和2型糖尿病密切相關(guān)，是代謝綜合征的組成部分之一。由于NAFLD發(fā)病機(jī)制的復(fù)雜性，目前尚無針對(duì)性的藥物治療。溶質(zhì)載體(solute carrier，SLC)轉(zhuǎn)運(yùn)蛋白與多種代謝性疾病有關(guān)，在肝臟中具有豐富表達(dá)，參與多種營養(yǎng)物質(zhì)和代謝產(chǎn)物的轉(zhuǎn)運(yùn)，調(diào)節(jié)營養(yǎng)供應(yīng)、代謝轉(zhuǎn)換、能量平衡和氧化應(yīng)激等，調(diào)控肝臟生理功能。尤為重要的是，其中部分SLC轉(zhuǎn)運(yùn)體已經(jīng)成為藥物開發(fā)的新靶標(biāo)。本文重點(diǎn)闡述SLC在營養(yǎng)物質(zhì)和肝臟代謝產(chǎn)物轉(zhuǎn)運(yùn)中的作用及其與NAFLD的相關(guān)性，并揭示SLC作為NAFLD新藥研發(fā)潛在靶標(biāo)的可能性，以期為治療NAFLD提供新的選擇。

非酒精性脂肪性肝??；溶質(zhì)載體SLC家族；糖脂代謝

代謝綜合征是由肥胖、高血糖、高甘油三酯、低高密度脂蛋白膽固醇水平和高血壓等組成的一組臨床表現(xiàn)，往往表現(xiàn)為多種代謝紊亂集于一身，且肥胖可成為這些代謝紊亂的共同誘因，目前靶向藥物治療很大一部分集中在肥胖與T2D。NAFLD與肥胖癥、T2D密切相關(guān)，是代謝綜合征的組成部分之一[1,2]。NAFLD是指除長期大量飲酒和其他明確的肝損傷因素外所引起的，以甘油三酯為主的脂質(zhì)在肝細(xì)胞中蓄積為病理特征的肝臟代謝性疾病，疾病譜包括單純性脂肪變性、非酒精性脂肪性肝炎(non-alcoholic steatohepatitis，NASH)、肝硬化和肝細(xì)胞癌。其中，NASH以炎癥、肝細(xì)胞損傷和肝纖維化為特征，可進(jìn)展為肝硬化和肝細(xì)胞癌[3]。流行病學(xué)調(diào)查顯示，NAFLD全球成人患病率超過25%，并且已成為中國最常見的肝臟疾病，呈現(xiàn)出年輕化的發(fā)病趨勢。預(yù)計(jì)到2030年底，我國NAFLD患者將達(dá)到3.14億[4]。NASH患者中約15%可發(fā)展為肝硬化、肝細(xì)胞癌等終末期肝病，后者是肝移植的主要原因，對(duì)人類生命健康造成威脅[5]。因此，深入探究NASH發(fā)生發(fā)展的分子機(jī)制對(duì)于靶向NASH藥物的研發(fā)和NASH患者的藥物干預(yù)治療均具有重要意義。

SLC家族包含400多種轉(zhuǎn)運(yùn)蛋白，這些轉(zhuǎn)運(yùn)蛋白介導(dǎo)離子、氨基酸、核苷酸和糖等小分子物質(zhì)跨生物膜流入和流出。SLC介導(dǎo)被動(dòng)和繼發(fā)性主動(dòng)轉(zhuǎn)運(yùn)，其中沿電化學(xué)梯度進(jìn)行的被動(dòng)轉(zhuǎn)運(yùn)不需要耗能[6]，而繼發(fā)性主動(dòng)轉(zhuǎn)運(yùn)與離子的順電化學(xué)梯度轉(zhuǎn)運(yùn)相耦合，成為SLC底物運(yùn)輸?shù)哪芰縼碓础＝閷?dǎo)物質(zhì)和驅(qū)動(dòng)離子向同一方向運(yùn)輸?shù)姆Q為共轉(zhuǎn)運(yùn)體(同向轉(zhuǎn)運(yùn)體)，而交換體(反向轉(zhuǎn)運(yùn)體)則向相反方向轉(zhuǎn)移物質(zhì)。例如，共轉(zhuǎn)運(yùn)體SLC5A1、SLC5A2分別介導(dǎo)上皮細(xì)胞和近端小管細(xì)胞Na+攝取和葡萄糖重吸收[7]，交換體SLC16A1編碼的質(zhì)子相關(guān)單羧酸轉(zhuǎn)運(yùn)蛋白負(fù)責(zé)單羧酸如乳酸和丙酮酸在質(zhì)膜上的交換[8]。SLC轉(zhuǎn)運(yùn)蛋白在肝臟、腎臟、大腦和腸道等代謝器官中具有較高的表達(dá)水平，可以感知和響應(yīng)細(xì)胞外營養(yǎng)物質(zhì)的濃度、激素水平和能量狀態(tài)的波動(dòng)，與糖脂代謝關(guān)系密切，在肝臟的功能穩(wěn)態(tài)調(diào)節(jié)中發(fā)揮關(guān)鍵作用。目前已知，超過80種SLC轉(zhuǎn)運(yùn)蛋白與人類疾病有關(guān)，包括肥胖和T2D[9]。值得注意的是，肝臟脂肪變性合并代謝異常易引起并發(fā)癥，而代謝綜合征又與NASH進(jìn)程密切相關(guān)，兩者相互促進(jìn)。當(dāng)前NAFLD相關(guān)藥物研究主要聚焦于NASH治療新策略的研發(fā)，目前在研新藥有200余種，其中我國在研新藥30余種[10]。然而，SLC蛋白如何受細(xì)胞內(nèi)外信號(hào)調(diào)節(jié)從而轉(zhuǎn)運(yùn)代謝底物，促進(jìn)細(xì)胞代謝并影響NAFLD的機(jī)制還有待更深入的研究。本文主要綜述了代謝底物轉(zhuǎn)運(yùn)體SLC在肝臟糖脂代謝和NAFLD發(fā)生發(fā)展過程中的相關(guān)研究和潛在價(jià)值，揭示了SLC轉(zhuǎn)運(yùn)蛋白作為NAFLD藥物靶標(biāo)的理論依據(jù)。

1 SLC基因家族成員的定位及生物學(xué)作用

SLC介導(dǎo)各種底物的跨膜運(yùn)輸，如無機(jī)離子、氨基酸、脂肪酸、神經(jīng)遞質(zhì)和糖類等，在細(xì)胞生理功能的維持中發(fā)揮重要作用。NAFLD相關(guān)SLC家族成員的細(xì)胞內(nèi)定位，生理功能和表達(dá)情況總結(jié)見表1。

2 SLC與NAFLD的相關(guān)性

2.1 單糖轉(zhuǎn)運(yùn)體SLC2/SLC5

葡萄糖是機(jī)體的主要能量來源，SLC2A家族葡萄糖轉(zhuǎn)運(yùn)體(glucose transporter member，GLUT)和SLC5A家族Na+-葡萄糖共轉(zhuǎn)運(yùn)體(sodium/ glucose cotransporter member，SGLT)參與處理葡萄糖和其他己糖的吸收、分布、排泄和代謝，維持全身葡萄糖穩(wěn)態(tài)[11]。幾乎所有SLC2A都在肝臟中表達(dá)，其中SLC2A1、SLC2A2、SLC2A4、SLC2A5、SLC2A8和SLC2A9在肝臟中的表達(dá)尤其豐富。胰腺細(xì)胞通過SLC2A2感知血糖濃度升高，并增加胰島素分泌。在胰島素作用下，SLC2A4轉(zhuǎn)移到質(zhì)膜，進(jìn)一步促進(jìn)胰島素與其受體結(jié)合，促進(jìn)葡萄糖轉(zhuǎn)運(yùn)到骨骼肌、脂肪組織和心臟細(xì)胞中加以利用。同時(shí)，SLC2A2和SLC2A4也介導(dǎo)肝臟對(duì)葡萄糖的攝取，而這兩種轉(zhuǎn)運(yùn)蛋白表達(dá)異常會(huì)降低葡萄糖攝取和利用效率，引起機(jī)體代償性地分泌過多胰島素而產(chǎn)生高胰島素血癥和高血糖癥，破壞肝臟胰島素和葡萄糖穩(wěn)態(tài)。

↑表示在NAFLD中上調(diào)，↓表示在NAFLD中下調(diào)。

SGLT以Na+與溶質(zhì)共轉(zhuǎn)運(yùn)為特征，介導(dǎo)葡萄糖從腎小管腔重新吸收到細(xì)胞內(nèi)，由ATP酶建立的Na+濃度梯度驅(qū)動(dòng)，可回收超過90%經(jīng)腎小球?yàn)V過的葡萄糖[12]。其中，SGLT1(又稱為SLC5A1)和SGLT2(又稱為SLC5A2)是上皮細(xì)胞葡萄糖轉(zhuǎn)運(yùn)的重要轉(zhuǎn)運(yùn)體，也是SLC5A家族的主要成員。SLC5A2負(fù)責(zé)腎小管系統(tǒng)大部分的葡萄糖重吸收，隨后，SLC5A1重吸收其余濾過的葡萄糖?；蛲蛔儗?dǎo)致葡萄糖和半乳糖吸收不良，而基因突變與糖尿病有關(guān)，該基因突變小鼠表現(xiàn)出體重減輕、糖尿、多尿，但血糖正常，沒有胰島素抵抗或腎功能障礙的跡象[7]。其他SLC5A家族成員如SLC5A10也可能具有調(diào)控代謝穩(wěn)態(tài)的潛力。

2.1.1 葡萄糖轉(zhuǎn)運(yùn)體SLC2A1/2/4/9和SLC5A1/2

SLC2A1是調(diào)節(jié)己糖轉(zhuǎn)運(yùn)的主要SLC2A家族成員，具有非常廣泛的底物特異性，可以運(yùn)輸多種醛糖[13]。在胚胎發(fā)育過程中，SLC2A1缺陷導(dǎo)致葡萄糖攝取減少，激活細(xì)胞凋亡，誘發(fā)肝壞死[14]。一致的是，表達(dá)水平在NAFLD患者肝臟中降低，而且敲除的THLE2細(xì)胞內(nèi)活性氧水平升高、油酸誘導(dǎo)的脂滴增多[15]。同樣，SLC2A2介導(dǎo)葡萄糖通過肝細(xì)胞膜的雙向轉(zhuǎn)運(yùn)，在NASH肝臟中表達(dá)降低[16]。體外研究表明，高糖培養(yǎng)的HepG2細(xì)胞中SLC2A2表達(dá)降低而磷酸烯醇丙酮酸羧激酶-1和6-磷酸葡萄糖激酶升高，并伴隨胰島素抵抗和脂質(zhì)沉積[17]。因此，SLC2A1和SLC2A2可能通過促進(jìn)肝臟糖酵解和抑制活性氧水平而阻礙NAFLD進(jìn)展。

SLC2A4介導(dǎo)骨骼肌和脂肪組織中胰島素調(diào)控的葡萄糖轉(zhuǎn)運(yùn)進(jìn)入細(xì)胞，肌肉和脂肪細(xì)胞含有的一種特殊細(xì)胞器GLUT4儲(chǔ)存囊泡(GLUT4 storage vesicle，GSV)受胰島素刺激后，在細(xì)胞表面融合并將SLC2A4蛋白插入質(zhì)膜?；蛉毕菪∈笠蚬趋兰『椭窘M織葡萄糖攝入減少而引發(fā)高血糖癥[18]，更重要的是，胰島素對(duì)該基因的調(diào)控不僅存在于特定的細(xì)胞類型如脂肪和肌肉細(xì)胞，也存在于肝臟細(xì)胞[19]。因此，SLC2A4在肌肉、脂肪和肝臟細(xì)胞中增加胰島素對(duì)葡萄糖的攝取，可能通過維持全身葡萄糖穩(wěn)態(tài)來緩解NAFLD。此外，尿酸轉(zhuǎn)運(yùn)體SLC2A9將葡萄糖和果糖轉(zhuǎn)運(yùn)至細(xì)胞內(nèi)，維持血漿尿酸和葡萄糖正常水平，SLC2A9肝臟特異性失活小鼠表現(xiàn)出嚴(yán)重的高尿酸血癥[20]，而高水平尿酸可誘導(dǎo)小鼠肝臟脂肪異常積累[21]，進(jìn)而可能增加患NAFLD風(fēng)險(xiǎn)。

由SLC5A1和SLC5A2介導(dǎo)的葡萄糖重吸收促進(jìn)NAFLD的發(fā)展過程，且目前研究主要集中在SLC5A2特異性抑制劑對(duì)NAFLD的治療作用。SLC5A2抑制可通過下調(diào)脂質(zhì)合成相關(guān)蛋白，上調(diào)脂肪酸氧化相關(guān)基因(比如PPARα和CPT1α)，保護(hù)L02和HepG2免受棕櫚酸誘導(dǎo)的細(xì)胞內(nèi)脂質(zhì)堆積所造成的毒性[22]?；蛟谛∈蟾闻K中有表達(dá)，尤其在肝巨噬細(xì)胞和T細(xì)胞中表達(dá)水平較高[23]。SLC5A2抑制通過改善全身胰島素抵抗，導(dǎo)致體重降低，同時(shí)減少白色脂肪組織[24]，也可通過促進(jìn)肝臟脂肪酸氧化、抑制脂肪合成來減少肝臟甘油二酯、甘油三酯和膽固醇含量，以減輕肝臟脂毒性[25]。臨床研究表明，SLC5A2抑制通過降低血糖、肝臟脂肪含量和體重來改善NAFLD患者肝臟功能。臨床前實(shí)驗(yàn)和臨床研究都表明SLC5A2抑制通過改善糖脂代謝，減少肝細(xì)胞氧化應(yīng)激、炎癥和細(xì)胞凋亡，從而減輕NAFLD程度[26]。

2.1.2 果糖轉(zhuǎn)運(yùn)體SLC2A2/5/8和SLC5A10

果糖特異性細(xì)胞膜轉(zhuǎn)運(yùn)蛋白SLC2A5在十二指腸、小腸和腎臟組織中高表達(dá)，在肝臟中表達(dá)水平相對(duì)較低。果糖經(jīng)小腸上皮細(xì)胞SLC2A5轉(zhuǎn)運(yùn)后進(jìn)入血液循環(huán)，由肝細(xì)胞SLC2A2攝取后經(jīng)過一系列酶促反應(yīng)生成二羥基丙酮磷酸和甘油醛-3-磷酸，促進(jìn)糖異生過程而導(dǎo)致血糖升高。果糖代謝中間產(chǎn)物也可通過激活碳水化合物反應(yīng)元件結(jié)合蛋白(carbohydrate response element-binding protein，ChREBP)和固醇調(diào)節(jié)元件結(jié)合蛋白-1C(sterol regulatory element-binding protein 1C，SREBP1C)促進(jìn)肝細(xì)胞脂肪合成[27]。SLC2A5與小腸中果糖運(yùn)輸高度相關(guān)，但也可能有助于肝細(xì)胞對(duì)果糖的攝取，果糖攝入過量也與肝臟表達(dá)增加有關(guān)，可引起線粒體氧化應(yīng)激和功能障礙，促進(jìn)肝臟炎癥反應(yīng)及NAFLD進(jìn)程[28]。此外，果糖攝入過量也可引起內(nèi)質(zhì)網(wǎng)應(yīng)激，促進(jìn)肝細(xì)胞凋亡[29]。相比于僅高脂飲食，高果糖高脂飲食模型有最接近人類NAFLD的病變特征，SLC2A5對(duì)于果糖攝取至關(guān)重要，并且通過升高血糖、增加肝臟脂肪含量來誘導(dǎo)NAFLD。

SLC2A8促進(jìn)葡萄糖和果糖轉(zhuǎn)運(yùn)進(jìn)入細(xì)胞內(nèi)，在肝臟中高度表達(dá)。SLC2A8缺陷的雌鼠表現(xiàn)出肝果糖首過代謝受損，敲除顯著阻斷HepG2的果糖攝取，這表明果糖轉(zhuǎn)運(yùn)到肝細(xì)胞部分是由SLC2A8介導(dǎo)的[30]。缺陷小鼠能夠抵抗高果糖飲食誘導(dǎo)的葡萄糖耐受不良和高血脂癥[31]。有趣的是，雌鼠比雄鼠更易受高果糖飲食影響而誘導(dǎo)肝臟脂肪含量增加，而且肝臟果糖激酶在雌性大鼠中顯著地被果糖攝入所誘導(dǎo)，而在雄性大鼠中則沒有[32]。進(jìn)一步研究表明，靶向敲除肝臟可通過增強(qiáng)脂肪酸氧化，顯著降低脂肪酸含量，減輕果糖誘導(dǎo)的內(nèi)質(zhì)網(wǎng)應(yīng)激和肝臟炎癥，對(duì)果糖誘導(dǎo)的NASH雌鼠肝損傷和炎癥具有預(yù)防作用[33]。

SLC5A10介導(dǎo)腎近端小管細(xì)胞的果糖重吸收，其缺陷可引起尿果糖排泄，減少果糖吸收。矛盾的是，缺陷小鼠尿液中有大量果糖排泄，伴隨著血漿甘油三酯和附睪脂肪水平的降低，但表現(xiàn)出更嚴(yán)重的果糖誘導(dǎo)的肝脂肪變性以及空腹高胰島素血癥，可能是因?yàn)镾LC5A10缺陷導(dǎo)致SREBP-1c前體活化入核并增加肝臟脂肪合成[34]，提示SLC5A10在NAFLD疾病進(jìn)程中的作用有待更深入的研究。

2.2 硫酸鹽/羧酸鹽轉(zhuǎn)運(yùn)體SLC13

SLC13家族Na+偶聯(lián)陰離子轉(zhuǎn)運(yùn)體介導(dǎo)三羧酸循環(huán)中間產(chǎn)物如檸檬酸、琥珀酸和α-酮戊二酸等由質(zhì)膜轉(zhuǎn)運(yùn)到細(xì)胞內(nèi)，調(diào)節(jié)這些代謝物在血漿、尿液和組織中的水平，從而調(diào)節(jié)糖脂代謝[35]。SLC13轉(zhuǎn)運(yùn)蛋白分為兩類：一類SLC13A1 (NaS1)和SLC13A4 (NaS2)運(yùn)輸硫酸鹽，另一類SLC13A2 (NaC1/NaDC1)、SLC13A3(NaC3/NaDC3)和SLC13A5 (NaC2/NaCT)運(yùn)輸羧酸鹽，這些轉(zhuǎn)運(yùn)蛋白主要在肝、腎、小腸和腦中表達(dá)[36]。

2.2.1 羧酸鹽轉(zhuǎn)運(yùn)體NaDC1、NaDC3和NaCT

編碼的Na+/二羧酸共轉(zhuǎn)運(yùn)體1 (Na+/ dicarboxylate cotransporter 1, NaDC1)在腎臟和小腸中表達(dá)尤高，分別從尿液和飲食中重吸收琥珀酸、α-酮戊二酸和檸檬酸等三羧酸循環(huán)中間產(chǎn)物，其重要功能是介導(dǎo)檸檬酸的重吸收，維持血液中酸堿平衡穩(wěn)態(tài)[37]。檸檬酸鹽通過抑制磷酸果糖激酶-1來抑制糖酵解，并通過刺激果糖-1,6-雙磷酸酶來激活糖異生，因此，細(xì)胞內(nèi)檸檬酸鹽水平的降低會(huì)刺激糖酵解并抑制糖異生[38]。檸檬酸鹽在胞漿中的代謝物乙酰輔酶A對(duì)于脂肪酸合成和蛋白質(zhì)乙?；己苤匾掖龠M(jìn)巨噬細(xì)胞活化[39]。高脂飲食小鼠肝臟基因表達(dá)下調(diào)，而二甲雙胍能上調(diào)飲食誘導(dǎo)肥胖小鼠肝臟的表達(dá)[40]，推測SLC13A2可能通過轉(zhuǎn)運(yùn)檸檬酸進(jìn)入細(xì)胞內(nèi)，升高細(xì)胞內(nèi)檸檬酸鹽水平，抑制肝臟糖酵解和促進(jìn)脂肪合成，可能加重NAFLD。

編碼的Na+/二羧酸共轉(zhuǎn)運(yùn)體3 (Na+/ dicarboxylate cotransporter 3, NaDC3)可轉(zhuǎn)運(yùn)α-酮戊二酸作為肝細(xì)胞內(nèi)谷氨酰胺合成的底物[41]，谷氨酰胺可降低高脂飲食誘導(dǎo)的肝臟氧化應(yīng)激程度，抑制肝臟脂肪變性，對(duì)NAFLD有一定的抑制作用[42]。此外，肥胖合并2型糖尿病大鼠肝臟中基因表達(dá)上調(diào)[43]，臨床研究表明，NAFLD合并肥胖患者血漿α-酮戊二酸水平升高[44]，提示SLC13A3可能轉(zhuǎn)運(yùn)α-酮戊二酸進(jìn)入細(xì)胞內(nèi)，促進(jìn)谷氨酰胺合成的同時(shí)抑制肝臟脂肪變性而減輕NAFLD。

編碼的Na+/檸檬酸共轉(zhuǎn)運(yùn)體(Na+/ citrate cotransporter, NaCT)對(duì)檸檬酸的親和力最高，其主要功能是將血液循環(huán)中的檸檬酸轉(zhuǎn)運(yùn)進(jìn)入細(xì)胞內(nèi)，參與利用細(xì)胞外檸檬酸鹽合成脂肪酸和膽固醇，促進(jìn)脂質(zhì)累積[45]。在肥胖、胰島素抵抗的NAFLD患者的肝臟樣本中表達(dá)顯著增加，并伴隨肝臟脂肪變性。基因敲除小鼠可抵抗高脂飲食和衰老誘導(dǎo)的肥胖、肝臟脂肪變性和胰島素抵抗[46]，同樣，基因敲除的人肝癌細(xì)胞系HepG2也顯示出檸檬酸鹽攝取及其分解代謝受損，脂質(zhì)水平降低[47]，提示SLC13A5具有類似于SLC13A2的抑制NAFLD作用。

2.2.2 硫酸鹽轉(zhuǎn)運(yùn)體NaS1

編碼的Na+/硫酸鹽共轉(zhuǎn)運(yùn)體1 (Na+/ sulfate cotransporter, NaS1)可促進(jìn)硫酸鹽在小腸的吸收和腎臟的重吸收，從而維持硫酸鹽血漿水平穩(wěn)態(tài)。缺陷被證明與肝損傷血清酶學(xué)指標(biāo)(血清轉(zhuǎn)氨酶丙氨酸氨基轉(zhuǎn)移酶和天冬氨酸氨基轉(zhuǎn)移酶)的水平升高密切相關(guān)[35]，而該基因缺失的小鼠表現(xiàn)出肝臟脂肪、血漿膽固醇和低密度脂蛋白增多，肝臟糖原含量減少[48]，提示SLC13A1缺失可能抑制肝臟糖異生并增加脂質(zhì)合成以誘發(fā)NAFLD。

2.3 單羧酸轉(zhuǎn)運(yùn)體SLC16

SLC16由單羧酸轉(zhuǎn)運(yùn)體(monocarboxylate transporter，MCT)家族的14個(gè)成員組成，在細(xì)胞營養(yǎng)物質(zhì)的運(yùn)輸、新陳代謝和酸堿平衡的調(diào)節(jié)中發(fā)揮重要作用。SLC16A1，SLC16A4，SLC16A10，SLC16A11和SLC16A13通過參與L-乳酸、丙酮酸、短鏈脂肪酸和其他單羧酸類物質(zhì)在各種組織中的質(zhì)子依賴性轉(zhuǎn)運(yùn)，與糖脂的動(dòng)態(tài)調(diào)節(jié)有關(guān)，可能影響NAFLD過程中糖、脂和氨基酸代謝[49]。

2.3.1 SLC16A1和SLC16A4

SLC16A1介導(dǎo)單羧酸鹽和酮體在肝細(xì)胞膜上的轉(zhuǎn)運(yùn)。糖酵解產(chǎn)生的乳酸是肝臟糖異生和脂肪生成的底物，肝臟通過SLC16A1和SLC16A4促進(jìn)乳酸的排出，維持細(xì)胞內(nèi)乳酸平衡，乳酸是TCA循環(huán)中的主要碳源，因此也是能量生成的主要碳源[50]。另外，糖酵解過程中產(chǎn)生的丙酮酸也是TCA循環(huán)中的主要碳源。在禁食情況下或生酮飲食時(shí)，肝臟酮體β-羥丁酸酯和乙酰乙酸酯大量生成，由SLC16A1轉(zhuǎn)運(yùn)出肝臟，可為大腦、心臟和骨骼肌提供能量[51]?；蚯贸∈罂赡芡ㄟ^抑制乳酸和丙酮酸外排，促進(jìn)糖酵解過程和TCA循環(huán)，抵抗高脂飲食誘導(dǎo)的肥胖，減輕胰島素抵抗和肝臟脂肪變性[52]。SLC16A4將單羧酸鹽轉(zhuǎn)入細(xì)胞內(nèi)，在肥胖、糖尿病和腎臟損傷患者中表達(dá)升高[53]，且高表達(dá)的NASH患者易轉(zhuǎn)變?yōu)楦鼑?yán)重的肝癌[54]，可能是SLC16A4將過多的乳酸鹽、丙酮酸鹽和酮體轉(zhuǎn)運(yùn)進(jìn)入細(xì)胞內(nèi)，脂質(zhì)積累異常所致。

2.3.2 SLC16A10

SLC16A10介導(dǎo)肝臟上皮細(xì)胞內(nèi)芳香族氨基酸流出，維持體內(nèi)循環(huán)中和肝臟中氨基酸水平[55]。NASH小鼠肝臟中下調(diào)，而且可能是NASH肝臟中芳香族氨基酸，尤其是酪氨酸和苯丙氨酸濃度增加的潛在原因[56]。因此，MCT10將氨基酸代謝與NAFLD聯(lián)系起來，可能部分通過調(diào)節(jié)血漿氨基酸水平和肝臟胰島素水平抑制NAFLD進(jìn)展[57]。

2.3.3 SLC16A11

SLC16A11在肝臟中高表達(dá)且主要定位于內(nèi)質(zhì)網(wǎng)，參與肝臟脂質(zhì)代謝過程。NAFLD的主要病理學(xué)特征是肝臟異常的脂質(zhì)積累，破壞肝細(xì)胞中內(nèi)質(zhì)網(wǎng)蛋白穩(wěn)態(tài)，導(dǎo)致炎癥損傷甚至細(xì)胞死亡[58]。人類原代肝細(xì)胞敲除后胞內(nèi)?；鈮A、二酰甘油和三酰甘油水平顯著增加，肝細(xì)胞以極低密度脂蛋白形式分泌的三酰甘油胞外水平也增加[59]。與之一致的是，NAFLD患者血漿和肝臟?；鈮A、二酰甘油和三酰甘油水平增加[60]。然而，敲除小鼠無顯著代謝缺陷，但在基因敲除小鼠的肝臟中重組2型糖尿病患者的突變體會(huì)導(dǎo)致更多的甘油三酯積累，誘導(dǎo)胰島素抵抗，而重組野生型不會(huì)造成甘油三酯積累和胰島素抵抗[61]。相反，敲低通過抑制血漿和肝臟甘油三酯蓄積，進(jìn)而改善高脂飲食喂養(yǎng)小鼠的葡萄糖耐量和肝臟胰島素信號(hào)傳導(dǎo)[62]。因此，SLC16A11在肝臟脂質(zhì)代謝中的作用十分復(fù)雜，可能通過影響肝臟中甘油三酯積累與NAFLD相聯(lián)系，其在NAFLD中的具體作用及機(jī)制值得進(jìn)一步的研究。

2.3.4 SLC16A13

SLC16A13在肝臟中高表達(dá)且主要定位于高爾基體，轉(zhuǎn)運(yùn)乳酸進(jìn)入細(xì)胞內(nèi)。高脂飲食喂養(yǎng)的基因敲除小鼠可能通過減少肝細(xì)胞內(nèi)乳酸供應(yīng)，導(dǎo)致AMP活化蛋白激酶(AMP-activated protein kinase, AMPK)激活，肝細(xì)胞線粒體氧化呼吸功能增強(qiáng)，胰島素敏感性增加，肝臟脂肪堆積減少[63]。此外，PPARα作為肝臟脂代謝的關(guān)鍵調(diào)節(jié)因子，其激動(dòng)劑可上調(diào)小鼠小腸和肝臟中基因的表達(dá)[64]。因此，SLC16A13可能通過細(xì)胞內(nèi)過量乳酸和脂肪堆積推動(dòng)NAFLD進(jìn)程。

2.4 有機(jī)陽離子和陰離子轉(zhuǎn)運(yùn)體SLC22

SLC22轉(zhuǎn)運(yùn)蛋白家族在肝臟、腎臟和腸道中高表達(dá)，可介導(dǎo)肝細(xì)胞中外源性有機(jī)離子的攝取，根據(jù)底物性質(zhì)分為3個(gè)亞家族：有機(jī)陽離子轉(zhuǎn)運(yùn)體(organic cation transporter, OCT)、有機(jī)陰離子轉(zhuǎn)運(yùn)體(organic anion transporter, OAT)和有機(jī)陽離子/肉堿轉(zhuǎn)運(yùn)體(organic cation/carnitine transporter, OCTN)。OCTs分布于各類組織，在親水性藥物的肝臟吸收中起重要作用[65]。OATs亞家族約占SLC22轉(zhuǎn)運(yùn)蛋白家族的一半，通過調(diào)節(jié)肝臟信號(hào)分子和關(guān)鍵代謝物水平而在細(xì)胞間通訊中發(fā)揮作用[66]，包括SLC22A7/9/12。OCTN是膜轉(zhuǎn)運(yùn)蛋白的一個(gè)小亞家族，可介導(dǎo)人腎臟和肝臟對(duì)肉堿的重吸收，從而升高血漿和肝臟組織肉堿水平，促進(jìn)線粒體脂肪酸β氧化[67]。

2.4.1 肉堿轉(zhuǎn)運(yùn)體SLC22A5

SLC22A5將肝臟細(xì)胞膜上L-肉堿轉(zhuǎn)運(yùn)至細(xì)胞內(nèi)，而且長鏈脂肪酸依賴于與L-肉堿的酯化反應(yīng)形成乙酰肉堿，以便從細(xì)胞質(zhì)運(yùn)輸?shù)骄€粒體基質(zhì)進(jìn)行氧化和能量產(chǎn)生[68]。L-肉堿還有另一個(gè)重要作用，即通過形成乙酰肉堿被轉(zhuǎn)運(yùn)出線粒體，緩沖線粒體中過量的乙酰輔酶A[69]。SLC22A5缺陷引起原發(fā)性肉堿缺乏癥，患者血清和肝細(xì)胞內(nèi)L-肉堿水平較低，導(dǎo)致脂肪酸氧化受阻，患者因完全依賴葡萄糖進(jìn)行能量代謝而出現(xiàn)低血糖[70]。原發(fā)性肉堿缺乏癥患者與NAFLD患者有相似的肝臟病理特征，表現(xiàn)為肝臟脂肪堆積、ALT和AST水平升高[71]。因此，SLC22A5通過提高肝細(xì)胞內(nèi)肉堿含量而促進(jìn)脂肪酸氧化，進(jìn)而抑制NAFLD。

2.4.2 有機(jī)陰離子轉(zhuǎn)運(yùn)體SLC22A7/9/12

SLC22A7在肝臟和腎臟中高表達(dá)，對(duì)環(huán)核苷酸例如環(huán)鳥苷單磷酸(cyclic guanosine monophosphate, cGMP)有較高的底物親和力[72]，可能在調(diào)節(jié)細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)過程中發(fā)揮作用。此外，煙酸和煙酰胺是煙酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucleotide, NAD+)的生物合成前體，主要由SLC22A7轉(zhuǎn)運(yùn)進(jìn)入肝細(xì)胞[73]。NAD+是一種重要的能量代謝氧化還原因子，也是還原型煙酰胺腺嘌呤二核苷酸磷酸(nicotinamide adenine dinucleotide Phosphate, NADPH)的前體，NADPH是抗氧化防御系統(tǒng)的重要組成部分。據(jù)此推測，SLC22A7轉(zhuǎn)運(yùn)NAD+前體進(jìn)入細(xì)胞內(nèi)，可能改善肝臟線粒體功能，降低氧化應(yīng)激，抑制肝星狀細(xì)胞激活，阻遏NASH進(jìn)程[74]。

SLC22A9是SLC22家族有機(jī)陰離子轉(zhuǎn)運(yùn)體成員中的第一個(gè)肝臟特異性轉(zhuǎn)運(yùn)體，只在肝臟中表達(dá)，并定位于肝細(xì)胞的竇狀膜上。SLC22A9介導(dǎo)S2細(xì)胞的丁酸攝取和硫酸雌酮外排[75]，且丁酸鈉已被證實(shí)可以改善高脂飲食誘導(dǎo)的肝臟炎癥和肝功能指標(biāo)ALT和AST，降低肝臟甘油三酯和膽固醇水平，減輕NAFLD[76]。此外，HNF-1α與基因啟動(dòng)子區(qū)域結(jié)合，促進(jìn)該基因表達(dá)，靶向敲低HNF-1α降低了Huh7細(xì)胞中表達(dá)[77]；HNF-1通過抑制PPARγ和SREBP1/2等脂肪生成相關(guān)基因的表達(dá)來抑制脂質(zhì)合成代謝，從而緩解NAFLD進(jìn)展[78]，推測可能通過增強(qiáng)HNF-1α對(duì)脂質(zhì)合成代謝的抑制作用而降低NAFLD風(fēng)險(xiǎn)。

SLC22A12在肝臟和棕色脂肪組織中表達(dá)，并在HFD小鼠棕色脂肪組織中表達(dá)上調(diào)而導(dǎo)致棕色脂肪白色化和脂質(zhì)積累，并增加了棕色脂肪組織活性氧的產(chǎn)生。的表達(dá)抑制可以減輕HFD誘導(dǎo)的肥胖小鼠肝脂肪變性，促進(jìn)富含脂質(zhì)的BAT重新褐變來改善胰島素抵抗，可能是伴有NAFLD的胰島素抵抗個(gè)體的新治療靶點(diǎn)[79]。

2.5 線粒體轉(zhuǎn)運(yùn)體SLC25

SLC25家族是SLC轉(zhuǎn)運(yùn)蛋白家族中最大的家族，由53個(gè)成員組成[80]。SLC25成員在其運(yùn)輸?shù)孜锏男再|(zhì)和大小、運(yùn)輸方式(單向、同向或反向)和驅(qū)動(dòng)力方面差異很大。SLC25轉(zhuǎn)運(yùn)體主要定位于線粒體內(nèi)膜，介導(dǎo)氨基酸、脂肪酸、輔因子、無機(jī)離子和核苷酸轉(zhuǎn)運(yùn)，參與多種代謝途徑，包括TCA循環(huán)、脂肪酸氧化和合成、糖酵解和糖異生、氨基酸分解等代謝過程[81]。

核苷酸轉(zhuǎn)運(yùn)體包括線粒體ADP/ATP載體SLC25A4、SLC25A5、SLC25A6、SLC25A31高表達(dá)于肝臟、腎臟和脂肪組織，將ADP輸入到線粒體基質(zhì)，并將產(chǎn)生的ATP輸出到細(xì)胞質(zhì)中，為細(xì)胞代謝提供能量[82]。SLC25與肝臟糖脂代謝相關(guān)研究相對(duì)缺乏，在NAFLD調(diào)控中可能有一定的潛力。

解偶聯(lián)蛋白(uncoupling protein, UCP)調(diào)節(jié)線粒體膜電位、能量消耗、活性氧產(chǎn)生和細(xì)胞氧化還原狀態(tài)。UCP介導(dǎo)質(zhì)子從膜間隙進(jìn)入線粒體基質(zhì)，從而破壞質(zhì)子梯度、降低膜電位[83]。UCP的表達(dá)和功能與代謝性疾病密切相關(guān)，UCP失調(diào)或功能障礙可能通過增加氧化應(yīng)激誘導(dǎo)的肝臟損傷而加劇NAFLD進(jìn)程[84]。

2.5.1 解耦聯(lián)蛋白SLC25A7/8/9

SLC25A7在棕色脂肪組織中高表達(dá)，解偶聯(lián)氧化磷酸化和ATP產(chǎn)生，將能量轉(zhuǎn)化為熱量。棕色脂肪組織產(chǎn)熱在動(dòng)物模型肥胖的發(fā)生中起關(guān)鍵作用，而SLC25A7功能障礙誘導(dǎo)小鼠模型肥胖的發(fā)生[85]。缺陷小鼠肝臟表現(xiàn)出細(xì)胞外琥珀酸含量升高，通過激活肝臟星狀細(xì)胞和巨噬細(xì)胞琥珀酸受體1來驅(qū)動(dòng)炎癥，加速NAFLD進(jìn)展[86]。白色脂肪細(xì)胞中SLC25A7受寒冷、藥物、營養(yǎng)和內(nèi)源性刺激誘導(dǎo)，促進(jìn)白色脂肪棕色化，另一方面，可能增強(qiáng)NAFLD小鼠肝臟線粒體呼吸功能，改善肝臟脂肪變性和胰島素抵抗[87]。小鼠棕色脂肪組織中脂滴外殼蛋白Perilipin 5在暴露于寒冷環(huán)境中顯著增加，維持線粒體嵴結(jié)構(gòu)完整性和促進(jìn)線粒體呼吸功能，而SLC25A7可能通過增強(qiáng)Perilipin 5對(duì)線粒體功能的促進(jìn)作用，改善全身糖耐量和高脂飲食誘導(dǎo)的肝脂肪變性[88]。因此，SLC25A7的線粒體解偶聯(lián)作用對(duì)于維持全身能量穩(wěn)態(tài)和治療肥胖相關(guān)NAFLD具有重要意義。

SLC25A8通過抑制線粒體中活性氧產(chǎn)生而發(fā)揮抗氧化功能，對(duì)于維持胰島細(xì)胞的功能至關(guān)重要[89]。糖尿病小鼠胰島β細(xì)胞中SLC25A8活性降低會(huì)增加ATP的產(chǎn)生和胰島素分泌，但同時(shí)增加的活性氧阻礙胰島β細(xì)胞分泌胰島素[90]。此外，肥胖小鼠胰島細(xì)胞中SLC25A8一方面抑制β細(xì)胞的葡萄糖依賴型胰島素分泌，另一方面增加能量消耗，從而降低肥胖的風(fēng)險(xiǎn)[91]。SLC25A8增加胰島素分泌，可能通過降低血糖濃度及促進(jìn)肝臟胰島素功能以緩解NAFLD。

SLC25A9與SLC25A8功能相似，同時(shí)可介導(dǎo)脂肪酸誘導(dǎo)的解偶聯(lián)，增強(qiáng)脂肪酸β氧化相關(guān)的中鏈?；o酶A-脫氫酶和過氧化物酶體增殖物激活受體-γ共激活因子-1α的基因表達(dá)，改善線粒體功能[92]，并可能通過抑制肝臟脂毒性而減輕NAFLD。

2.5.2 三羧酸循環(huán)中間產(chǎn)物轉(zhuǎn)運(yùn)體SLC25A1/ 10/11/13/20/24

線粒體檸檬酸鹽轉(zhuǎn)運(yùn)體SLC25A1將檸檬酸從線粒體基質(zhì)轉(zhuǎn)運(yùn)到胞漿，且在NASH肝臟中高表達(dá)。肝臟特異性敲除可以降低細(xì)胞內(nèi)檸檬酸水平，減弱PPARγ信號(hào)傳導(dǎo)，并抑制脂質(zhì)合成和糖異生基因的表達(dá)，改善糖耐量，減少肝臟炎性巨噬細(xì)胞浸潤，同時(shí)顯著減輕由高脂肪飲食引起的肥胖[93]。

SLC25A10主要在白色脂肪組織中表達(dá)，其次在肝臟中表達(dá)，通過線粒體內(nèi)膜將蘋果酸鹽轉(zhuǎn)運(yùn)進(jìn)入線粒體，將檸檬酸鹽從線粒體轉(zhuǎn)運(yùn)至胞漿，脂肪組織或肝臟細(xì)胞漿中的脂肪合成由檸檬酸鹽轉(zhuǎn)運(yùn)開始，肥胖小鼠白色脂肪組織中表達(dá)顯著增加，以檸檬酸鹽為原料合成脂肪[94]。抑制SLC25A10則顯著減少了HepG2和3T3-L1細(xì)胞中檸檬酸從線粒體到胞漿的運(yùn)輸，降低了ACC1表達(dá)和丙二酰輔酶A水平，抑制脂肪合成[95]；過表達(dá)導(dǎo)致3T3-L1線粒體超極化而產(chǎn)生活性氧[96]。另一方面，琥珀酸經(jīng)過從線粒體基質(zhì)轉(zhuǎn)運(yùn)到胞質(zhì)，作用于琥珀酸受體1并通過抑制cAMP-磷酸化激素敏感脂肪酶途徑來抑制脂肪分解。白色脂肪細(xì)胞特異性敲除導(dǎo)致脂肪細(xì)胞脂解增強(qiáng)，并促進(jìn)HFD誘導(dǎo)的小鼠肝脂毒性和全身胰島素抵抗，而脂肪細(xì)胞特異性過表達(dá)通過減少肝臟游離脂肪酸的攝取而減輕肝脂毒性，同時(shí)改善葡萄糖耐量和胰島素敏感性[97]。SLC25A10可能主要通過抑制肝臟脂肪合成而作為治療NAFLD的靶標(biāo)。

SLC25A11參與蘋果酸-天冬氨酸穿梭，部分介導(dǎo)分離的大鼠肝臟線粒體攝取谷胱甘肽，以及H4IIE的谷胱甘肽從細(xì)胞質(zhì)轉(zhuǎn)運(yùn)到線粒體，抵抗過氧化氫誘導(dǎo)的細(xì)胞毒性[98]；此外，SLC25A11介導(dǎo)α-酮戊二酸和其他二羧酸鹽的交換[99]，將α-酮戊二酸從線粒體轉(zhuǎn)移到胞漿，α-酮戊二酸通過抑制相關(guān)限速酶直接抑制肝臟糖異生，也可以進(jìn)入細(xì)胞核內(nèi)，與基因啟動(dòng)子區(qū)域結(jié)合，且肝臟特異性敲除可消除α-酮戊二酸對(duì)PEPCK、G6Pase和FBP蛋白表達(dá)和活性的抑制作用[100]，提示SLC25A11可能通過介導(dǎo)肝臟細(xì)胞中α-酮戊二酸和谷胱甘肽穿過線粒體進(jìn)行交換，減少肝細(xì)胞線粒體氧化應(yīng)激并抑制糖異生而減輕NAFLD癥狀。

2.5.3 天冬氨酸-谷氨酸轉(zhuǎn)運(yùn)體SLC25A13

SLC25A13介導(dǎo)細(xì)胞漿谷氨酸轉(zhuǎn)運(yùn)至線粒體，天冬氨酸從線粒體轉(zhuǎn)運(yùn)至細(xì)胞漿，天冬氨酸是尿素、蛋白質(zhì)合成，乳酸糖異生以及細(xì)胞內(nèi)NADH氧化所必需的[101,102]。作為肝臟中唯一的天冬氨酸-谷氨酸轉(zhuǎn)運(yùn)體，SLC25A13缺陷降低肝臟精氨酸琥珀酸合成酶的活性，導(dǎo)致高氨血癥[103]，基因功能缺陷患者表現(xiàn)出肝脂肪變性和脂肪性肝炎[104]。SLC25A13對(duì)肝臟脂肪的調(diào)控機(jī)制尚不明確，可能通過增加細(xì)胞漿中天冬氨酸來源的草酰乙酸，促進(jìn)糖酵解，隨后生成的蘋果酸經(jīng)SLC25A11轉(zhuǎn)運(yùn)至線粒體促進(jìn)TCA循環(huán)，抑制NAFLD進(jìn)展。

2.5.4 肉堿轉(zhuǎn)運(yùn)體SLC25A20

SLC25A20介導(dǎo)胞漿酰基肉堿進(jìn)入線粒體及線粒體內(nèi)游離肉堿轉(zhuǎn)移到胞漿，胞漿中肉堿棕櫚酰基轉(zhuǎn)移酶1將?；鶑囊阴］o酶A轉(zhuǎn)移到肉堿，通過SLC25A20將?；鈮A轉(zhuǎn)移至線粒體，然后通過肉堿棕櫚?；D(zhuǎn)移酶2將?；鶑孽；鈮A轉(zhuǎn)移到線粒體內(nèi)的輔酶A，生成的乙酰輔酶A在線粒體中經(jīng)過β氧化，為機(jī)體代謝提供能量[105]。SLC25A20促進(jìn)肝臟脂肪酸氧化，改變肝臟脂代謝譜，可能抑制NAFLD過程。

2.5.5 ATP-鎂/磷酸鹽轉(zhuǎn)運(yùn)體SLC25A24

SLC25A24介導(dǎo)ATP-鎂和磷酸鹽在線粒體基質(zhì)和胞漿之間的交換，以及腺嘌呤核苷酸通過線粒體內(nèi)膜的攝取或流出[106]。當(dāng)細(xì)胞溶質(zhì)鈣水平升高時(shí)，SLC25A24將腺嘌呤核苷酸輸入線粒體基質(zhì)，一方面控制線粒體基質(zhì)腺嘌呤核苷酸水平以響應(yīng)細(xì)胞能量需求，另一方面可能通過促進(jìn)線粒體基質(zhì)中磷酸鈣沉淀物形成，從而緩沖線粒體基質(zhì)中鈣水平[107]。在應(yīng)激條件下，腺嘌呤核苷酸進(jìn)出線粒體對(duì)于維持呼吸功能和防止鈣誘導(dǎo)的線粒體內(nèi)膜通透性增加是必要的。高脂飲食誘導(dǎo)小鼠白色脂肪組織和肝臟中基因表達(dá)水平升高，該基因敲除小鼠可能通過激活肝細(xì)胞內(nèi)鈣離子信號(hào)通路，促進(jìn)氧化分解代謝，進(jìn)而抵抗HFD誘導(dǎo)的肥胖，表現(xiàn)為體重和白色脂肪組織重量明顯降低[108]。

2.6 脂肪酸轉(zhuǎn)運(yùn)體SLC27

SLC27脂肪酸轉(zhuǎn)運(yùn)體(fatty acid transport protein，F(xiàn)ATP)可存在于細(xì)胞膜和細(xì)胞質(zhì)，可作為長鏈脂肪酸(long chain fatty acids，LCFA)的直接轉(zhuǎn)運(yùn)體，或作為通過酰基輔酶A合成酶(acyl coenzyme A synthetase，ACS)活性作用于LCFA的酶。ACS催化LCFA轉(zhuǎn)化為?；o酶A硫代酯，從而激活LCFA。然后，激活的LCFA可被細(xì)胞用于許多代謝過程，如脂肪酸合成、氧化和磷脂合成[109]。與SLC2A類似，SLC27的細(xì)胞內(nèi)定位是動(dòng)態(tài)的，SLC27可以響應(yīng)胰島素信號(hào)而從細(xì)胞質(zhì)轉(zhuǎn)移到質(zhì)膜[110]，具有攝取和活化LCFA的雙重功能。

SLC27A2主要在肝臟和腎臟表達(dá)，過表達(dá)可增加肝臟脂肪酸攝取和ACS活性[111]，肝臟特異性SLC27A2缺失的小鼠肝細(xì)胞對(duì)LCFA的攝取減少，過氧化物酶體中的ACS活性降低，且SLC27A2缺失能夠抑制高脂飲食誘導(dǎo)的肝脂肪變性并改善胰島素敏感性，可能是治療NAFLD的新靶點(diǎn)[112]。

SLC27A5僅在肝臟中表達(dá)，特別是在肝細(xì)胞的基底膜中作為脂肪酸轉(zhuǎn)運(yùn)蛋白發(fā)揮作用。肝臟敲除導(dǎo)致小鼠肝臟甘油三酯和脂肪酸含量降低[113]，且通過減少食物攝入量和增加能量消耗而降低高脂飲食導(dǎo)致的體重增加[114]，降低肝臟三酯含量和血糖水平。SLC27A5在早期NAFLD患者中的表達(dá)增加，抑制SLC27A5可能成為治療NAFLD的一種新方法。

2.7 鋅轉(zhuǎn)運(yùn)體

SLC30家族中最主要的成員基因的產(chǎn)物鋅轉(zhuǎn)運(yùn)體8(Zinc Transporter 8, ZnT8)表達(dá)在胰腺β細(xì)胞的胰島素分泌顆粒膜上，將鋅離子從細(xì)胞質(zhì)輸送到胰島素分泌顆粒中，為胰島素合成提供鋅，并且維持胰島素的成熟、儲(chǔ)存和穩(wěn)定性。與胰島素協(xié)同分泌的鋅通過抑制網(wǎng)格蛋白依賴性胰島素內(nèi)吞作用來抑制肝臟胰島素清除，因此β細(xì)胞特異性敲除小鼠的胰島素清除能力增強(qiáng)，外周血胰島素水平降低[115]。HFD喂養(yǎng)的全身基因敲除小鼠表現(xiàn)出明顯增加的肥胖、高血糖、胰島素抵抗和葡萄糖不耐受；而β細(xì)胞特異性敲除小鼠則表現(xiàn)出高血糖、胰島素合成分泌不足和葡萄糖不耐受，其體重與對(duì)照組相似，表明僅β細(xì)胞中的不會(huì)顯著增加體重，可能因?yàn)橐脖磉_(dá)在胰腺α細(xì)胞并抑制β細(xì)胞功能[116]。適度降低ZnT8活性可以降低β細(xì)胞鋅分泌，增強(qiáng)肝臟胰島素清除率；相反，ZnT8活性嚴(yán)重降低可能增加β細(xì)胞胰島素分泌[117]。因此，針對(duì)ZnT8的藥物干預(yù)可能產(chǎn)生較為復(fù)雜的結(jié)果，體現(xiàn)在對(duì)肝臟胰島素水平和葡萄糖穩(wěn)態(tài)的調(diào)控方面，同時(shí)對(duì)于NAFLD的治療也有一定的提示作用。

3 SLC介導(dǎo)治療NAFLD的天然產(chǎn)物或藥物

目前SLC家族成員參與的NAFLD治療主要集中在葡萄糖轉(zhuǎn)運(yùn)體，另外，三羧酸循環(huán)底物轉(zhuǎn)運(yùn)體也占很大比例，部分代表性天然產(chǎn)物或藥物見表2。其中，恩格列凈、PF-06649298和L-肉堿作為底物可直接與SLC結(jié)合以調(diào)控相應(yīng)的轉(zhuǎn)運(yùn)體活性，為其他SLC靶向藥物的研發(fā)提供參考和經(jīng)驗(yàn)；而其他天然產(chǎn)物或藥物通過信號(hào)傳導(dǎo)途徑間接影響SLC的表達(dá)和活性，有助于深入研究SLC的上游調(diào)控過程，為SLC作為NAFLD治療藥物靶點(diǎn)提供完整和詳細(xì)的理論依據(jù)。

表2 SLC介導(dǎo)治療NAFLD的天然產(chǎn)物或藥物

↑表示上調(diào)SLC，↓表示下調(diào)SLC。

針對(duì)NAFLD的已上市和在研藥物中，PPAR激動(dòng)劑占很大比例，且部分通過調(diào)控SLC表達(dá)而改善疾病進(jìn)展。全球僅有印度批準(zhǔn)上市首款也是唯一一款NASH治療藥物Saroglitazar，是PPARα/γ的雙重激動(dòng)劑，減少肝臟和血漿中甘油三酯，增強(qiáng)胰島素敏感性，緩解NASH患者代謝異常[133]。已進(jìn)入Ⅲ期臨床試驗(yàn)的NASH在研新藥中，Lanifibranor是一種非選擇性PPAR受體激動(dòng)劑，可同時(shí)激活α、δ、γ3種受體，促進(jìn)葡萄糖的利用，減少肝臟中炎癥因子的表達(dá)和內(nèi)質(zhì)網(wǎng)應(yīng)激肝臟中的炎癥反應(yīng)[134]。Aramchol是一種膽酸與花生酸的結(jié)合物，抑制人類原代肝細(xì)胞脂肪合成關(guān)鍵酶SCD1，同時(shí)上調(diào)保護(hù)性基因PPARγ的表達(dá)，減輕肝臟炎癥反應(yīng)，為Aramchol用于NASH患者的臨床治療提供了理論依據(jù)[135,136]。值得注意的是，PPAR激動(dòng)劑的廣泛激動(dòng)效應(yīng)在發(fā)揮治療作用的同時(shí)也不可避免地引發(fā)非預(yù)期結(jié)果，給藥物研發(fā)帶來困難和挑戰(zhàn)，而SLC作為糖、脂、氨基酸代謝物轉(zhuǎn)運(yùn)體，其靶向設(shè)計(jì)藥物可直接通過改變代謝物水平以改善代謝紊亂，對(duì)于NAFLD的防治具有重要意義。

4 結(jié)語與展望

NAFLD與肥胖、T2D聯(lián)系密切，然而目前NAFLD與SLC的相關(guān)研究還不夠深入，因此本綜述主要從兩方面介紹NAFLD與SLC的關(guān)系：一方面總結(jié)現(xiàn)有研究SLC家族成員在NAFLD的作用及機(jī)制；另一方面總結(jié)參與到肥胖、T2D中SLC的作用機(jī)制，尋找與NAFLD相關(guān)的糖脂代謝表型和信號(hào)通路，推測其他尚未研究的SLC在NAFLD中可能扮演的角色。同時(shí)需要注意的是，針對(duì)肥胖或T2D的有效防治也可能有利于NAFLD的防治。

人類代謝性疾病相關(guān)的SLC家族轉(zhuǎn)運(yùn)蛋白中，SLC5A2是唯一已經(jīng)確證的治療代謝性疾病的SLC特異性靶點(diǎn)，有4種抑制劑已獲FDA批準(zhǔn)用于2型糖尿病的臨床治療，可以降低葡萄糖水平、體重、血壓和肝臟脂肪含量，同時(shí)對(duì)于NAFLD的治療具有潛在有益作用。盡管已有文獻(xiàn)報(bào)道多種SLC家族成員參與糖脂代謝過程(圖1)，調(diào)控代謝性疾病進(jìn)展，且與肝臟脂肪變性、炎癥反應(yīng)有關(guān)，但在肝臟代謝中的作用及機(jī)制還有待深入研究。同時(shí)，缺乏結(jié)構(gòu)表征也阻礙了靶向SLC小分子化合物的設(shè)計(jì)，這也是未來其作為NAFLD防治靶點(diǎn)需要攻克的難點(diǎn)。然而，單一靶點(diǎn)的藥物治療效果有限，結(jié)合SLC家族在糖、脂轉(zhuǎn)運(yùn)中的底物多樣性，針對(duì)不同發(fā)病機(jī)制和轉(zhuǎn)運(yùn)體設(shè)計(jì)多靶點(diǎn)藥物將有助于從代謝物轉(zhuǎn)運(yùn)的角度理解NAFLD的發(fā)病機(jī)制，為藥物研發(fā)提供更詳細(xì)和有力的理論依據(jù)。

圖1 SLC參與調(diào)控糖脂代謝過程

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Progress of solute carrier SLC family in nonalcoholic fatty liver disease

Zhiquan Tang, Li Shi, Jing Xiong

Nonalcoholic fatty liver disease is closely related to obesity and type 2 diabetes mellitus, and is one of the components of metabolic syndrome. Due to the complexity of its pathogenesis, there is no effective drug treatment to date. Solute carrier transporters are associated with a variety of metabolic diseases and are abundantly expressed in the liver. They participate in the transport of a variety of nutrients and metabolites, regulate nutrient supply, metabolic transformation, energy balance and oxidative stress, and modulate the physiological functions of liver. Particularly, it is important that some of these SLC transporters have become new targets for drug development. In this review, we summarize the role of SLC in the transport of nutrients and liver metabolites and its correlation with NAFLD, and reveal the potential of SLC as a target for the development of new drugs for NAFLD treatment so as to provide a new choice for the treatment of the disease.

nonalcoholic fatty liver disease; solute carrier SLC family; glucose and lipid metabolism

2022-07-16;

2022-09-22;

2022-09-30

國家自然科學(xué)基金項(xiàng)目(編號(hào)：82070883，82273982)，江蘇省自然科學(xué)基金項(xiàng)目(編號(hào)：BK20221525)和中國藥科大學(xué)高層次人才科研啟動(dòng)項(xiàng)目資助[Supported by the National Natural Science Foundation of China (Nos. 82070883, 82273982), the National Natural Science Foundation of Jiangsu Province (No. BK20221525), and the Scientific Research Foundation for High-level Faculty, China Pharmaceutical University]

湯志全，在讀碩士研究生，專業(yè)方向：藥理學(xué)。E-mail: 1350312679@qq.com

熊晶，博士，研究員，研究方向：靶向代謝穩(wěn)態(tài)研究肝臟疾病的分子機(jī)制與藥物干預(yù)。E-mail: jxiong@cpu.edu.cn

10.16288/j.yczz.22-238

(責(zé)任編委: 孟卓賢)