梁佳琦，劉暢，張雯翔，陳思禹

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肝臟分泌因子與代謝性疾病

梁佳琦，劉暢，張雯翔，陳思禹

中國藥科大學(xué)生命科學(xué)與技術(shù)學(xué)院，南京 211198

代謝性疾病泛指代謝功能發(fā)生問題所引起的疾病，其主要癥狀包括中心性肥胖、胰島素抵抗、血脂血糖異常、血壓升高等。肝臟作為人體內(nèi)一個重要的代謝器官，在調(diào)節(jié)全身葡萄糖和脂質(zhì)代謝等許多生理過程中起關(guān)鍵作用。近年來的大量研究表明，肝臟可以合成和分泌多種生物信號分子，如FGF21、Fetuin-A以及ANGPTL8等，以自分泌/旁分泌的方式調(diào)節(jié)機體的代謝過程。干預(yù)相關(guān)肝臟分泌因子的表達(dá)可有助于預(yù)防、診斷和治療代謝性疾病。然而，目前肝臟分泌因子與代謝穩(wěn)態(tài)之間的互作機制仍不明確。本文對不同肝臟分泌因子與代謝性疾病的關(guān)系展開論述，以期為治療代謝性疾病提供新的策略和參考。

肝臟分泌因子；代謝性疾病；診斷治療

近年來，隨著經(jīng)濟的騰飛與生活節(jié)奏的改變，不健康的飲食模式和久坐不動的生活方式導(dǎo)致代謝性疾病的患病率顯著提高，已成為威脅全球人類健康的重要因素。代謝性疾病是由體內(nèi)氨基酸、糖脂代謝紊亂引發(fā)的一類疾病，其癥狀主要包括中心性肥胖、胰島素抵抗、血脂血糖異常、血壓升高等，是誘發(fā)心腦血管疾病、內(nèi)分泌系統(tǒng)疾病的重要危險因素[1]。肝臟作為體內(nèi)重要的代謝器官，近年來已被證實具有重要的內(nèi)分泌功能。它能通過產(chǎn)生多種功能性的肝臟分泌因子(表1)，如FGF21、Fetuin-A以及ANGPTL4等，已陸續(xù)被證實具有重要的代謝調(diào)控功能，其與肝脂肪變性、炎癥信號傳導(dǎo)、胰島素抵抗等有關(guān)[2]。它們能以內(nèi)分泌、自分泌及旁分泌方式，建立起組織器官間的良性對話秩序。各個器官組織之間的通訊和相互調(diào)控對維持機體代謝穩(wěn)態(tài)至關(guān)重要。本文對不同肝臟分泌因子與代謝性疾病的關(guān)系展開綜述，以期為治療代謝性疾病提供新的策略。

1 成纖維細(xì)胞生長因子家族(fibroblast growth factors, FGFs)

FGFs是一類多肽生長因子，分子量約為17～ 34 kDa，F(xiàn)GF家族由22個不同成員組成，具有13%～71%的氨基酸同源性。在脊椎動物中，F(xiàn)GFs在基因水平和氨基酸序列上都高度保守，其結(jié)構(gòu)中具有兩個保守的半胱氨酸殘基，對肝素/硫酸肝素具有高親和力[19]。FGFs控制胚胎發(fā)育和成體生物體中的多種生理反應(yīng)。在發(fā)育過程中，F(xiàn)GFs通過控制細(xì)胞增殖、存活、遷移和分化在模式形成和形態(tài)發(fā)生中發(fā)揮關(guān)鍵作用[20～22]。在成體生物中，F(xiàn)GFs參與組織修復(fù)、維持能量及代謝穩(wěn)態(tài)[23,24]。在FGF家族的22個成員中，F(xiàn)GF15/19、FGF21和FGF23構(gòu)成了FGF19亞家族，它們作為內(nèi)分泌激素調(diào)節(jié)膽汁酸、脂肪酸、葡萄糖和無機鹽代謝。其中，F(xiàn)GF15/19是一種在小腸回腸腸上皮細(xì)胞中表達(dá)的腸道激素，并在餐后響應(yīng)膽汁酸吸收而釋放[25,26]。FGF23主要由骨組織中的成骨細(xì)胞和骨細(xì)胞分泌，主要調(diào)節(jié)全身磷酸鹽穩(wěn)態(tài)和維生素D代謝[27,28]。FGF21主要在肝臟中表達(dá)，作為一種肝臟分泌因子，在能量調(diào)節(jié)代謝過程發(fā)揮重要作用[29]。

1.1 FGF21

Nishimura等[30]于2000年首次在小鼠胚胎中分離出FGF21，其在小鼠和人類之間約有75%的氨基酸序列同源性。在生理條件下，血液中的FGF21主要來源于肝臟[31]。除此之外，F(xiàn)GF21在脂肪組織、胰腺、肌肉中也均有少量表達(dá)[29]。

表1 肝臟分泌因子的主要特征

FGF21在調(diào)節(jié)能量平衡和維持葡萄糖和脂質(zhì)穩(wěn)態(tài)方面具有重要作用[32]。在肥胖和糖尿病動物模型中，F(xiàn)GF21可在不影響總熱量攝入下導(dǎo)致體重減輕、血漿葡萄糖和甘油三酯(triglyceride, TG)水平降低，并提高機體胰島素敏感性[33]。此外，在胰島素抵抗?fàn)顟B(tài)下(如脂肪肝、肥胖和2型糖尿病)，血清FGF21水平會升高。因此，F(xiàn)GF21也可作為糖尿病的預(yù)測因子或生物標(biāo)志物[34]。

FGF21主要通過影響肝臟、脂肪組織和中樞神經(jīng)系統(tǒng)發(fā)揮其內(nèi)分泌作用。在肝臟中，F(xiàn)GF21降低胰島素抵抗，增強脂肪氧化，降低TG水平及肝細(xì)胞中脂滴的積累[35,36]。在脂肪組織中，一方面，F(xiàn)GF21通過增強脂肪組織胰島素敏感性來促進(jìn)葡萄糖利用并增加能量消耗[37,38]。另一方面，暴露于寒冷或運動后，F(xiàn)GF21會誘導(dǎo)過氧化物酶體增殖物激活受體γ共激活因子-1α(peroxisome proliferator activated receptor γ coactivator-1α, PGC-1α)的上調(diào)，從而促進(jìn)脂肪組織和骨骼肌的產(chǎn)熱[39]。在中樞神經(jīng)系統(tǒng)中，F(xiàn)GF21可以提高下丘腦促腎上腺皮質(zhì)激素釋放因子的表達(dá)，刺激交感神經(jīng)活動，進(jìn)而促進(jìn)棕色脂肪組織中的能量消耗[40]。此外，F(xiàn)GF-21還具有抗炎作用。研究表明，在非酒精性脂肪性肝炎(nonalcoholic steatohepatitis, NASH)小鼠模型中，F(xiàn)GF21可通過調(diào)節(jié)脂聯(lián)素抑制Th17細(xì)胞分化和IL-17A表達(dá)來緩解炎癥[41]。

雖然FGF21可以對肥胖等相關(guān)代謝性疾病發(fā)揮較好的藥理學(xué)作用。然而，由于其藥代動力學(xué)和生物物理特性較差，天然的FGF21并不適合臨床使用。目前，已經(jīng)開發(fā)出大量針對FGFR1-β-klotho受體復(fù)合物的長效FGF21類似物和激動性單克隆抗體，一些FGF21類似物和模擬物已進(jìn)入肥胖、2型糖尿病和NASH患者臨床試驗的早期階段[24]。FGF21類似物的靶向遞送，以及FGF21組織特異性受體激動劑的開發(fā)，將有助于提高基于FGF21的藥物療法的療效和安全性。

2 血管生成素樣蛋白家族 (angiopoietin- like proteins, ANGPTL)

ANGPTL是一種與血管生成素結(jié)構(gòu)相似的蛋白質(zhì)家族。迄今為止，已發(fā)現(xiàn)8個ANGPTL亞型，即ANGPTL1至ANGPTL8。其中，ANGPTL3、ANGPTL4和ANGPTL8主要在肝臟中表達(dá)。近年來，許多研究表明ANGPTLs在生理和病理過程中發(fā)揮著關(guān)鍵的調(diào)節(jié)作用，在糖脂代謝、炎癥、造血和癌癥的發(fā)生發(fā)展中都有一定的生物學(xué)功能[42～44]。

2.1 ANGPTL3

ANGPTL3僅在肝臟中產(chǎn)生，因此可以歸類為真正的肝臟特異性分泌因子[45]。ANGPTL3作為一種血漿TG的調(diào)節(jié)劑，對脂蛋白脂肪酶(lipoprotein lipase, LPL)的活性具有抑制作用，該酶錨定在毛細(xì)血管內(nèi)皮上，并催化TG水解生成脂肪酸[46]。小鼠中ANGPTL3的失活可降低血漿TG和游離脂肪酸水平并抑制動脈粥樣硬化[47,48]。在人體內(nèi)，ANGPTL3突變可導(dǎo)致低密度脂蛋白(low density lipoprotein, LDL)、高密度脂蛋白和TG的血漿水平降低，誘發(fā)家族聯(lián)合性低血脂癥[49]。此外，ANGPTL3功能喪失的突變雜合子攜帶者患冠狀動脈疾病的風(fēng)險低于非攜帶者[50,51]。

目前，美國Regeneron公司開發(fā)了一種靶向ANGPTL3的C末端LPL抑制結(jié)構(gòu)域的單克隆抗體Evinacumab。在最近的臨床三期試驗中，高膽固醇血癥患者使用24周的Evinacumab治療后，顯著降低了體內(nèi)LDL和TG含量[52]?？傊?，ANGPTL3是血漿脂蛋白代謝的重要肝源性調(diào)節(jié)劑。未來抗ANGPTL3的治療將成為降低特定患者血漿中LDL和TG的有效治療策略。

2.2 ANGPTL4

與ANGPTL3一樣，ANGPTL4在調(diào)節(jié)脂質(zhì)儲存和分解方面具有重要作用[53]。基因在人類等哺乳動物中高度保守，與小鼠具有77%的氨基酸序列相似性[54]。其通過依賴C端纖維蛋白原樣結(jié)構(gòu)域增加脂肪細(xì)胞的脂解作用，并通過N端卷曲螺旋結(jié)構(gòu)域抑制LPL的活性[53,55]。ANGPTL4在肝臟和脂肪組織中的表達(dá)在進(jìn)食和禁食后發(fā)生改變，表明ANGPTL4在調(diào)節(jié)脂肪代謝中發(fā)揮作用。它通過抑制LPL活性并增加脂肪細(xì)胞中TG的分解，從而減輕脂肪組織重量[56]。在小鼠中，腺病毒介導(dǎo)的ANGPTL4過表達(dá)可以改善葡萄糖耐量并減少肝葡萄糖輸出[57]。

ANGPTL4在胰島素功能及血糖控制方面的作用存在爭議。一些研究認(rèn)為盡管在ANGPTL4過表達(dá)的小鼠中有嚴(yán)重的肝臟脂肪變性，但它們的肝臟和全身胰島素敏感性有所改善[57]。同時，ANGPTL4增強胰島素介導(dǎo)的糖異生抑制過程從而降低原代肝細(xì)胞中的肝葡萄糖產(chǎn)生，并且在人體內(nèi)，ANGPTL4水平與胰島素敏感性正相關(guān)[57]。與此相反的是，另一些研究表明ANGPTL4基因敲除小鼠可降低血脂，減少肝臟和肌肉中的脂質(zhì)積累，增強胰島素信號傳導(dǎo)，并改善血糖[58,59]。因此，未來需要進(jìn)一步深入研究來探尋這些差異背后的原因，以確定ANGPTL4在調(diào)節(jié)血糖、血脂中的潛在治療價值。

2.3 ANGPTL8

ANGPTL8，又稱Betatrophin、RIFL、Lipasin或TD26，是一種由人基因(小鼠同源基因)編碼的分泌蛋白，是ANGPTL蛋白家族的新成員，ANGPTL8參與機體脂質(zhì)代謝、炎癥、癌細(xì)胞侵襲和造血干細(xì)胞活性的調(diào)控[60～62]。與其他ANGPTLs相比，ANGPTL8缺乏纖維蛋白原/血管生成素樣結(jié)構(gòu)域[63]。在小鼠中，ANGPTL8主要在脂肪組織和肝臟中表達(dá)。在人體內(nèi)，其主要表達(dá)部位是肝臟，在脂肪組織中僅有少量表達(dá)[64]。研究顯示，ANGPTL8在各種代謝性疾病的發(fā)生發(fā)展中起關(guān)鍵作用。例如，1/2型糖尿病患者的血清ANGPTL8蛋白水平升高，并且重度肥胖患者和2型糖尿病患者的總膽固醇、LDL和載脂蛋白B的含量與ANGPTL8蛋白水平呈正相關(guān)[65]。在給予高脂進(jìn)食后，小鼠的肝臟、棕色和白色脂肪組織中ANGPTL8的mRNA被顯著誘導(dǎo)。同時，在小鼠體內(nèi)用腺病毒過表達(dá)ANGPTL8會增加血清TG水平[66]。此外，ANGPTL8的表達(dá)還受禁食/再進(jìn)食信號的調(diào)控。在空腹?fàn)顟B(tài)下ANGPTL8水平降低，而在再進(jìn)食狀態(tài)下顯著增加[67]。本研究組發(fā)現(xiàn)，ANGPTL8作為肝臟分泌因子可重設(shè)小鼠肝臟時鐘和代謝基因的晝夜節(jié)律，是一種響應(yīng)食物信號的肝臟時鐘關(guān)鍵調(diào)節(jié)器。從機制上講，ANGPTL8的重置功能依賴于膜受體PirB的信號傳遞、激酶和轉(zhuǎn)錄因子的磷酸化，從而瞬時激活中樞時鐘基因Per1[5]。這些結(jié)果提示肝臟分泌因子ANGPTL8能響應(yīng)食物信號，以“自分泌”形式，參與肝臟糖脂代謝穩(wěn)態(tài)的調(diào)節(jié)過程。

3 血管非炎性蛋白-1(Vanin-1)

Vanin-1是由肝小葉中肝實質(zhì)細(xì)胞表達(dá)分泌的一種酶，作為機體氧化應(yīng)激的感受器，其本質(zhì)是一種泛酰巰基乙胺酶[68]。本研究組發(fā)現(xiàn)Vanin-1的表達(dá)和酶活在饑餓和db/db糖尿病小鼠肝臟中顯著升高，并通過減弱肝實質(zhì)細(xì)胞中Insulin/Akt信號通路活性，持續(xù)激活肝糖異生進(jìn)程，誘發(fā)機體高血糖癥和胰島素抵抗[69]。這一結(jié)果提示肝臟Vanin-1是糖尿病藥物研發(fā)的潛在新型靶標(biāo)。為了拓展Vanin-1的病理生理學(xué)功能，本研究組進(jìn)一步在白色脂肪組織中展開研究，發(fā)現(xiàn)Vanin-1表達(dá)和酶活在肥胖病人的白色脂肪中均降低，且與脂質(zhì)水解調(diào)節(jié)基因甘油三酯脂酶(adipose triglyceride lipase, ATGL)和激素敏感性甘油三酯脂酶(hormone-sensitive lipase, HSL)的表達(dá)呈顯著正相關(guān)性。更重要的是，Vanin-1的全身性缺失加劇了高脂食物誘發(fā)的小鼠腹部脂肪堆積和胰島素抵抗進(jìn)程[70]。這一結(jié)果提示白色脂肪中Vanin-1的降低是高脂食物誘發(fā)代謝性疾病的重要原因之一，且細(xì)胞內(nèi)的非分泌Vanin-1同樣具有重要的代謝調(diào)節(jié)功能。

相關(guān)研究表明Vanin-1還在許多代謝途徑的調(diào)節(jié)中起作用。研究發(fā)現(xiàn)Vanin-1是小鼠肝臟中過氧化物酶體增殖物激活受體α(peroxisome proliferator activated receptor α, PPARα)的調(diào)控靶點之一，口服PPARα激動劑類藥物能顯著誘導(dǎo)Vanin-1的表達(dá)[71]。此外，Vanin-1還調(diào)節(jié)著肝臟的氧化應(yīng)激。對乙酰氨基苯酚(APAP)是最常用的藥物之一，其安全性較高。然而，當(dāng)大量服用時，APAP會導(dǎo)致肝小葉中心肝細(xì)胞嚴(yán)重壞死，而Vanin-1在小鼠中可以保護(hù)肝臟免受APAP帶來的肝毒性。與野生型小鼠相比，缺乏Vanin-1的小鼠對APAP造成的肝損傷更敏感，并且表現(xiàn)出血漿谷丙轉(zhuǎn)氨酶濃度增加和更多的肝細(xì)胞壞死[72]。以上結(jié)果提示著Vanin-1在代謝穩(wěn)態(tài)維持中的重要性，未來還需要進(jìn)一步研究Vanin-1在不同器官中發(fā)揮何種(病理)生理作用。

4 胎球蛋白家族(Fetuin)

Fetuin家族是一種主要在肝臟分泌的糖蛋白，分為Fetuin-A和Fetuin-B。1944年P(guān)edersen首次在牛血清中發(fā)現(xiàn)并分離得到一種酸性糖蛋白，命名為Fetuin-A。隨后的半個世紀(jì)中陸續(xù)證明了Fetuin-A在骨骼重塑、神經(jīng)系統(tǒng)發(fā)育等生物過程中都具有重要作用[73]。直到2000年，哺乳動物Fetuin家族的第2個成員Fetuin-B才被發(fā)現(xiàn)[74]。與Fetuin-A相比，F(xiàn)etuin-B的氨基酸序列無顯著改變，蛋白結(jié)構(gòu)域具有高度同源性、半胱氨酸殘基也具有整體保守性，故屬于Fetuin-A的旁系同源物[74]。目前越來越多的研究顯示，F(xiàn)etuin家族在代謝性疾病的發(fā)生發(fā)展中扮演著重要的作用。

4.1 Fetuin-A

Fetuin-A，也稱為alpha2-Heremans-Schmid，主要由肝實質(zhì)細(xì)胞合成，然后釋放到血液中，是一種大小約為46 kDa的肝臟分泌因子[75]。Fetuin-A水平受多種飲食因素的影響。據(jù)報道，膳食中的Omega-3脂肪酸攝入可能會增加Fetuin-A的濃度，而乳制品、姜黃素、煙酸、棕櫚酸酯、咖啡和酒精等一些營養(yǎng)素會降低它的釋放[76]。近年來，許多研究證明了Fetuin-A在代謝疾病中的重要作用。例如，有研究表明Fetuin-A可以作為代謝性疾病的標(biāo)志物[77]。臨床結(jié)果顯示，體內(nèi)較高的Fetuin-A水平與2型糖尿病、肥胖及其相關(guān)并發(fā)癥之間存在密切聯(lián)系[78～80]。此外，F(xiàn)etuin-A在葡萄糖耐量、胰島素抵抗和肝纖維化中發(fā)揮重要作用。Fetuin-A基因敲除小鼠的葡萄糖和胰島素耐量試驗表明葡萄糖清除率和胰島素敏感性顯著增強，并且可以防止高脂飲食(high fat diet, HFD)誘導(dǎo)的代謝紊亂。其機制與小鼠肝臟和骨骼肌中胰島素受體及下游信號分子絲裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)和蛋白激酶B(protein kinase B, PKB/Akt)的磷酸化水平增加有關(guān)[81]。這些研究結(jié)果表明，F(xiàn)etuin-A可能在調(diào)節(jié)葡萄糖代謝、胰島素敏感性、體重增加和脂質(zhì)堆積方面發(fā)揮重要作用，并且可能是治療2型糖尿病、肥胖和其他胰島素抵抗疾病的新型治療靶點。

4.2 Fetuin-B

Fetuin-B是Fetuin家族的第二個成員，與Fetuin-A一樣，主要由肝臟產(chǎn)生并抑制胰島素受體酪氨酸激酶活性[74]。在小鼠中，F(xiàn)etuin-B可以促進(jìn)肝細(xì)胞產(chǎn)生胰島素抵抗，導(dǎo)致小鼠葡萄糖耐受不良[82]。在人體內(nèi)，患有脂肪肝和2型糖尿病的肥胖人群血漿Fetuin-B水平升高[83]。研究已表明，生理濃度的Fetuin-B會降低培養(yǎng)中的肌肉和肝細(xì)胞的胰島素敏感性，并且在這種情況下，它不能激活促炎信號傳導(dǎo)[84]?？傊?，以上這些發(fā)現(xiàn)為評估Fetuin-B在代謝性疾病的病理生理過程中的作用提供了理論依據(jù)，為疾病的早期診斷以及藥物干預(yù)提供新的靶點并開辟新的視角。

5 非轉(zhuǎn)移性黑色素瘤糖蛋白B(glycoprotein nonmetastatic melanoma protein B, GPNMB)

GPNMB是一種跨膜糖蛋白，于1995年首次發(fā)現(xiàn)在低轉(zhuǎn)移特性的黑色素瘤細(xì)胞系中高度表達(dá)[85]。GPNMB由位于基因座7p15的基因編碼，通過可變剪接形成2種亞型，分別包含572和560個氨基酸[86]。GPNMB錨定于細(xì)胞膜，其大部分結(jié)構(gòu)位于胞膜外。GPNMB的細(xì)胞外部分具有12個糖基化位點、一個多囊腎病結(jié)構(gòu)域(PKD)和一個整合素識別基序(RGD)[87]。GPNMB可被金屬蛋白酶ADAM10切割，釋放可與許多受體結(jié)合并引發(fā)細(xì)胞反應(yīng)的可溶性片段[88]。

炎性疾病會大量誘導(dǎo)GPNMB的產(chǎn)生，而健康組織中GPNMB表達(dá)量非常低[89]。與正常人體內(nèi)相比，2型糖尿病患者的血漿GPNMB水平升高并且GPNMB血清水平與肥胖及代謝參數(shù)(如臀圍、體重指數(shù)和胰島素抵抗)呈正相關(guān)[90, 91]。當(dāng)小鼠全身性敲除基因后，除了會導(dǎo)致肥胖外，還會引起代謝綜合征，如脂肪組織炎癥升高、胰島素抵抗和肝纖維化等[92]。武漢大學(xué)宋保亮課題組利用小鼠模型和人群樣本，發(fā)現(xiàn)由肝臟分泌的GPNMB蛋白通過與CD44結(jié)合刺激脂肪細(xì)胞中的脂肪生成，激發(fā)PI3K-AKT-mTOR-SREBP1c信號通路從而參與肥胖及胰島素抵抗的病程。而運用抗體中和等方法降低血液中的GPNMB可以有效抑制脂肪組織合成脂質(zhì)的能力，提高機體能量消耗，減輕肥胖并改善胰島素抵抗[90]。這些結(jié)果表明，GPNMB作為一種肝臟分泌因子可以調(diào)節(jié)脂肪生成作用，因此針對GPNMB的調(diào)控可能是一種治療肥胖和糖尿病的策略。

6 Adropin

Adropin是一種高度保守的由76個氨基酸組成的激素，由能量穩(wěn)態(tài)相關(guān)基因(energy homeostasis associated gene, ENHO)編碼，主要由肝臟和大腦分泌，其表達(dá)會隨著肝臟脂質(zhì)利用率的升高而降低，可調(diào)節(jié)許多組織中的能量代謝穩(wěn)態(tài)[93]。肥胖人群和2型糖尿病患者的血清Adropin水平較低，高脂進(jìn)食會降低肝臟脂肪變性小鼠ENHO的表達(dá)[94, 95]。Adropin敲除小鼠的肝臟脂肪變性加劇，并伴有全身水平的葡萄糖耐量和胰島素敏感性降低[96]。同時，在Adropin過表達(dá)的小鼠中高脂進(jìn)食誘導(dǎo)的肝脂肪變性得到緩解，且全身胰島素敏感性和葡萄糖耐量增強，脂肪酸氧化水平降低[93]。因此，Adropin的表達(dá)和分泌可以改善胰島素敏感性和脂質(zhì)代謝，同時抑制肝脂肪變性。這些研究表明，恢復(fù)肥胖患者肝臟和/或血液中的Adropin水平可能是治療非酒精性脂肪肝(nonalcoholic fatty liver disease, NAFLD)和胰島素抵抗的潛在方法。

7 Tsukushi

Tsukushi(TSK)是哺乳動物中高度保守的蛋白多糖，在肥胖小鼠和NASH模型中表達(dá)量顯著增加[97]。相關(guān)研究表明，該分泌蛋白在小鼠代謝旺盛情況下(如低溫環(huán)境或甲狀腺激素處理)會被顯著上調(diào)。當(dāng)能量攝入過多時，TSK的敲除能夠更好的調(diào)節(jié)體重和能量代謝平衡。TSK的缺失增加脂肪組織中交感神經(jīng)支配和去甲腎上腺素的釋放，介導(dǎo)脂肪組織的產(chǎn)熱，改善飲食誘導(dǎo)的肥胖從而促進(jìn)小鼠的能量消耗[98]。此外，TSK敲除小鼠減少肝臟的TG水平、緩解炎癥及肝臟纖維化進(jìn)程并抑制飲食誘導(dǎo)的肥胖，這可能是由于全身代謝的改善而不是針對促炎、促纖維化或胰島素信號通路的直接作用來介導(dǎo)的[97]。然而，TSK在NAFLD中的調(diào)控作用仍存在爭議。Mouchiroud[99]等的研究證明TSK對維持全身膽固醇穩(wěn)態(tài)有重要作用，TSK能降低循環(huán)中HDL含量并減少肝臟中膽固醇向膽汁酸的轉(zhuǎn)化，但TSK不會影響NAFLD的發(fā)展進(jìn)程且不會改變飲食誘導(dǎo)的體重。未來的研究應(yīng)尋找特定的TSK受體，以進(jìn)一步明確TSK在NAFLD中的功能及其在外周組織脂質(zhì)代謝和胰島素信號傳導(dǎo)中的作用。

8 白細(xì)胞衍生趨化因子2(LECT2)

LECT2最早由Yamagoe等[100]在PHA激活的人T細(xì)胞白血病SKW-3細(xì)胞中分離出來，是一種分子量大小為16 kDa的新型中性粒細(xì)胞趨化因子，由基因編碼并主要在肝臟中表達(dá)。在小鼠體內(nèi)，當(dāng)肥胖小鼠從HFD轉(zhuǎn)變?yōu)槌Ｒ?guī)飲食(regular diet，RD)后，體重與血清LECT2水平下降。同時，從RD到HFD的轉(zhuǎn)換迅速提高了小鼠血清LECT2水平。進(jìn)一步研究發(fā)現(xiàn)，血清LECT2水平與肝臟TG含量呈正相關(guān)，但與脂肪組織重量無關(guān)[101]。此外，LECT2全身敲除小鼠骨骼肌胰島素敏感性提高，其機制可能是增強了胰島素刺激下AKT的磷酸化。相反，LECT2的回補則激活JNK信號通路，并通過增加胰島素受體底物1(insulin receptor substrate 1, IRS1)的磷酸化來抑制胰島素信號傳導(dǎo)[102, 103]。總之，這些研究表明LECT2可能在代謝性疾病中發(fā)揮關(guān)鍵作用，它可能是代謝性疾病的潛在生物標(biāo)志物和治療靶點。

9 肝細(xì)胞衍生纖維蛋白原相關(guān)蛋白1(Hepassocin)

Hepassocin也稱為HFREP1或纖維蛋白原樣蛋白1，由肝細(xì)胞分泌，可促進(jìn)細(xì)胞生長和增殖[104]。最近研究發(fā)現(xiàn)HFREP1與NAFLD以及全身胰島素抵抗有關(guān)。HFREP1水平在NAFLD患者中升高，并且體內(nèi)循環(huán)濃度與血漿葡萄糖水平和胰島素抵抗正相關(guān)。HFREP1通過細(xì)胞外信號調(diào)節(jié)激酶ERK1/2依賴性途徑抑制胰島素信號傳導(dǎo)以誘導(dǎo)胰島素抵抗。此外，HFREP1肝臟敲低的小鼠改善了HFD小鼠和ob/ob小鼠的胰島素抵抗[105]。HFREP1的水平還受到不同營養(yǎng)信號的調(diào)節(jié)。油酸可通過轉(zhuǎn)錄激活因子3信號傳導(dǎo)來增加HepG2細(xì)胞中HFREP1表達(dá)，而棕櫚酸處理的原代肝細(xì)胞可以通過C/EBPβ介導(dǎo)的轉(zhuǎn)錄激活誘導(dǎo)HFREP1表達(dá)，并進(jìn)一步促進(jìn)骨骼肌中的胰島素抵抗進(jìn)程[106,107]。綜上所述，減少體內(nèi)循環(huán)HFREP1的含量可能是治療胰島素抵抗的可行方法。

10 中腦星形膠質(zhì)細(xì)胞源性神經(jīng)營養(yǎng)因子(mesencephalic astrocyte-derived neurotrophic factor, MANF)

MANF是一種新型保守的神經(jīng)營養(yǎng)因子，能夠通過內(nèi)質(zhì)網(wǎng)應(yīng)激而分泌[108]。最新的研究表明，MANF在維持機體代謝穩(wěn)態(tài)中發(fā)揮重要作用。研究顯示，與對照組小鼠相比，10個月大的MANF雜合子小鼠表現(xiàn)為更為嚴(yán)重的肝臟炎癥表型和肝損傷。相反，MANF的回補可以防止飲食引起的肝脂肪變性，改善衰老引起的小鼠的肝損傷、炎癥和代謝功能障礙[109]。因此在代謝應(yīng)激期間維持高M(jìn)ANF水平可以作為防止肝臟脂肪變性和炎癥發(fā)展的保護(hù)性干預(yù)措施。此外，MANF在肝臟特異性過表達(dá)促進(jìn)腹股溝皮下脂肪發(fā)生褐變并減輕了飲食誘導(dǎo)的肥胖、胰島素抵抗和肝臟脂肪變性。從機制上講，MANF通過p38-MAPK途徑直接促進(jìn)白色脂肪細(xì)胞發(fā)生褐變[110]。該研究揭示了MANF作為肝臟分泌因子在調(diào)節(jié)脂肪組織產(chǎn)熱中的關(guān)鍵作用，有望成為肥胖和相關(guān)代謝紊亂的潛在治療靶點。

11 骨形態(tài)發(fā)生蛋白9(bone morphogenic protein 9, BMP9)

BMP9，也稱為生長分化因子2(growth differentiation factor 2, GDF2)，主要在肝臟中表達(dá)，并分泌到小鼠和人類的血漿中，調(diào)節(jié)許多生物過程，如間充質(zhì)干細(xì)胞分化、血管生成、神經(jīng)發(fā)生、軟骨形成和腫瘤發(fā)生等[111～113]。Um等[114]研究表明當(dāng)小鼠冷暴露3周后，肝臟BMP9表達(dá)和血漿水平顯著增加。冷暴露可通過激活cAMP反應(yīng)元件結(jié)合蛋白(cAMP response-element binding protein, CREB)和CREB??結(jié)合蛋白誘導(dǎo)肝臟BMP9表達(dá)從而加速脂肪細(xì)胞發(fā)生褐變。綜上所述，BMP9作為一種在寒冷條件下發(fā)揮作用的新型肝臟分泌因子，有望成為預(yù)防和治療肥胖以及代謝疾病的有力藥理學(xué)靶標(biāo)。

12 妊娠區(qū)帶蛋白(pregnancy zone protein, PZP)

PZP是一種高度依賴雌激素的免疫血漿蛋白，含有多個蛋白酶的識別位點，在人類妊娠期間的表達(dá)顯著升高[115]。Lin等[15]發(fā)現(xiàn)，小鼠和人體的血清和肝臟中PZP的蛋白表達(dá)量在進(jìn)食后顯著增加。研究顯示，在飲食誘導(dǎo)下PZP與小鼠棕色脂肪(brown adipose tissue, BAT)中的受體GRP78蛋白(glucose regulated protein of 78 kDa)結(jié)合，形成器官間的信號傳導(dǎo)。其通過激活BAT中的p38 MAPK-ATF2信號通路促進(jìn)BAT的產(chǎn)熱，減輕機體重量，并改善了相關(guān)的代謝紊亂。該研究揭示了間歇性飲食條件下肝臟與BAT之間相互作用的分子機制，為以調(diào)控產(chǎn)熱為靶點而防治肥胖提供了重要的依據(jù)，有望得以實現(xiàn)臨床轉(zhuǎn)化，為治療減重提供新策略。

13 結(jié)語與展望

長期以來，肝臟作為體內(nèi)一個重要的代謝器官長期受到科學(xué)界重視，其在凝血、解毒、代謝、免疫、消化吸收等方面都發(fā)揮重要作用[116,117]。一些解剖、結(jié)構(gòu)和功能特征同時也證明了肝臟是組織間通訊的重要器官。肝臟接受約25%的心輸出量，提供大量血液，肝細(xì)胞和非實質(zhì)細(xì)胞將產(chǎn)物分泌到肝竇中，這些產(chǎn)物通過中央靜脈流向下腔靜脈，最終流向心臟后重新分配到外周組織。由于肝臟控制調(diào)節(jié)全身葡萄糖和脂質(zhì)代謝穩(wěn)態(tài)，因此其在代謝性疾病扮演著關(guān)鍵作用。例如，在NAFLD發(fā)病過程中發(fā)生肝臟脂肪變性可引起肝臟胰島素抵抗，從而導(dǎo)致血糖升高和2型糖尿病的發(fā)生發(fā)展。肝臟還通過釋放肝臟分泌因子來調(diào)節(jié)其他組織中的葡萄糖代謝和胰島素作用，而患有代謝性疾病后會改變肝臟蛋白質(zhì)組的分泌，從而促進(jìn)胰島素抵抗和其他代謝并發(fā)癥的發(fā)生(圖1)。

越來越多的研究表明，肝臟分泌因子在機體代謝及能量調(diào)控方面發(fā)揮著重要作用，它們可以通過以下一項或多項來調(diào)節(jié)整個生物體的能量平衡過程：(1)增加胰島素敏感性；(2)增加葡萄糖攝取；(3)降低血漿甘油三酯水平、調(diào)節(jié)膽固醇穩(wěn)態(tài)；(4)降低食物攝入量、減輕體重；(5)激活脂肪細(xì)胞增加能量消耗。因此適當(dāng)?shù)馗深A(yù)相關(guān)肝臟分泌因子的表達(dá)，有助于預(yù)防、診斷和治療代謝性疾病。目前，已有部分針對肝臟分泌因子開發(fā)的藥物已用于臨床試驗。例如，IONIS-ANGPTL3-LRx作為一種靶向人ANGPTL3 mRNA編碼序列內(nèi)的反義寡核苷酸藥物，可降低ANGPTL3蛋白表達(dá)量和相關(guān)脂蛋白水平，且沒有發(fā)現(xiàn)治療相關(guān)的不良事件[118]。此外，使用FGF21類似物L(fēng)Y2405319對肥胖和2型糖尿病患者進(jìn)行治療，發(fā)現(xiàn)該藥物具有改善血脂異常、促進(jìn)體重降低、降低空腹胰島素水平等療效[119]。但目前關(guān)于這類藥物的安全性、耐受性、藥代動力學(xué)和藥效學(xué)的數(shù)據(jù)很少，因此未來應(yīng)繼續(xù)進(jìn)行相關(guān)試驗來探索未知領(lǐng)域從而促進(jìn)臨床轉(zhuǎn)化。

圖1 肝臟分泌因子通過運輸?shù)竭h(yuǎn)端組織發(fā)揮系統(tǒng)作用

在胰腺中，F(xiàn)etuin-A破壞β細(xì)胞功能成熟，而ANGPTL8促進(jìn)β細(xì)胞增殖；FGF21調(diào)節(jié)腹內(nèi)側(cè)下丘腦的蔗糖攝入量；在血管和肺部，F(xiàn)etuin-A抑制血管鈣化和肺部腫瘤生長；在肌肉中，Adropin通過抑制平滑肌細(xì)胞增殖，LECT2、HFREP1和Fetuin-B誘導(dǎo)骨骼肌產(chǎn)生胰島素抵抗；在脂肪組織中，PZP激活BAT促進(jìn)產(chǎn)熱，TSK抑制BAT活性減少產(chǎn)熱，MANF和BMP9促進(jìn)WAT褐變，ANGPTL4加速脂肪細(xì)胞中脂質(zhì)的分解，GPNMB刺激脂肪細(xì)胞中的脂質(zhì)生成。在心臟中，Adropin改善內(nèi)皮細(xì)胞功能，F(xiàn)etuin-A抑制心臟中鈣鹽的形成和積累；此外，F(xiàn)etuin-A可以抑制腎結(jié)石的形成。

雖然已陸續(xù)發(fā)現(xiàn)數(shù)種肝臟分泌因子并在其與代謝性疾病的關(guān)系研究中取得了實質(zhì)性的進(jìn)展，但該領(lǐng)域仍面臨一些挑戰(zhàn)。第一個挑戰(zhàn)是如何對靶細(xì)胞/靶器官的信號接收或響應(yīng)能力進(jìn)行評估。事實上，由于靶器官/靶細(xì)胞的差異，不同的肝臟分泌因子在發(fā)揮生理功能時存在極大的不同。因此，在臨床上不僅要考慮特殊情況下肝臟分泌因子的變化差異，還需要對其運輸途徑及靶器官的信號接收或響應(yīng)能力進(jìn)行評估，尤其是在多種復(fù)雜的肝臟分泌因子共同作用的情況下，這一現(xiàn)象使得進(jìn)一步研究工作變得十分艱難。第二個挑戰(zhàn)是探究代謝性疾病如何調(diào)節(jié)肝臟分泌因子的變化。研究表明，脂肪變性過程中會發(fā)生轉(zhuǎn)錄重編程，但通過內(nèi)質(zhì)網(wǎng)和高爾基體調(diào)節(jié)蛋白質(zhì)加工的機制尚不清楚。第三個也是最重要的臨床挑戰(zhàn)是能否確定一種或一組肝源性分泌因子來預(yù)測或者診斷代謝性疾病的發(fā)生發(fā)展過程。此外，上述分泌因子還存著肝臟是否是其唯一分泌器官的差異，如Adropin，也在大腦中分泌。且在不同生理/病理情況下，對單一因子在多器官分泌的調(diào)節(jié)往往更加難以操作。解決這些挑戰(zhàn)與問題將加深人們對于代謝性疾病發(fā)病機制的理解，并從肝臟分泌因子的角度開發(fā)有效的治療手段。

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Interaction between hepatokines and metabolic diseases

Jiaqi Liang, Chang Liu, Wenxiang Zhang, Siyu Chen

Metabolic diseases are broadly defined as diseases caused by problems in metabolic function, including central obesity, insulin resistance, lipid glucose abnormalities, and elevated blood pressure. As an important metabolic organ, the liver plays a key role in regulating many physiological processes such as systemic glucose and lipid metabolism. Numerous studies in recent years have shown that the liver can synthesize and secrete a variety of hepatokines, including FGF21, Fetuin-A and ANGPTL8, which regulate the metabolism in an autocrine/paracrine manner. Intervention of hepatokines expression may contribute to the prevention, diagnosis and treatment of metabolic diseases. However, further studies are needed to be investigated as the mechanism of hepatokines and metabolic homeostasis is still elusive. In this review, we summarize the relationships between hepatokines and metabolic diseases in order to provide new strategies for the treatment of metabolic diseases.

hepatokines; metabolic diseases; diagnosis and therapy

2022-06-27;

2022-09-06;

2022-09-20

國家自然科學(xué)基金(編號：31800992)和江蘇省自然科學(xué)基金(編號： BK20180554)資助[Supported by the Natural Science Foundation of China (No. 31800992) and the Natural Science Foundation of JiangSu (No. BK20180554)]

梁佳琦，在讀碩士研究生，專業(yè)方向：病理生理學(xué)，細(xì)胞生物學(xué)。E-mail: 3221030939@stu.cpu.edu.cn

陳思禹，博士，副教授，研究方向：代謝性疾病的干預(yù)靶標(biāo)及先導(dǎo)藥物發(fā)現(xiàn)。E-mail: siyuchen@cpu.edu.cn

10.16288/j.yczz.22-218

(責(zé)任編委: 孟卓賢)