色素上皮衍生因子與胰島素抵抗的關(guān)系（綜述） - 李翔

1、.徐 州 醫(yī) 學(xué) 院色素上皮衍生因子與胰島素抵抗的關(guān)系（綜述）作者：李翔（ 徐州醫(yī)學(xué)院神經(jīng)生物學(xué)研究中心，江蘇 徐州 221000 ）摘 要：色素上皮衍生因子（Pigment epithelium-derived factor，PEDF）是具有多種生理活性的糖蛋白，包括抗血管新生、降低血管通透性、抗腫瘤以及神經(jīng)營(yíng)養(yǎng)活性。最近研究表明PEDF能夠調(diào)節(jié)糖代謝和脂代謝，與胰島素抵抗的有一定的聯(lián)系。本文主要就PEDF引起胰島素抵抗這方面的研究做一綜述，闡述了PEDF與代謝性疾病的廣泛聯(lián)系，并總結(jié)了PEDF引起胰島素抵抗的可能機(jī)制。關(guān) 鍵 詞：PEDF；代謝；胰島素抵抗；機(jī)制The realations

2、hips of PEDF and insulin resistance（Review）Li Xiang( XuZhou Medical College-Research Center for Neurobiology,221000)Abstract:Pigment epithelium-derived factor (PEDF) is a glycoprotein with a variety of physiological activities including anti-angiogenic,anti-vasopermeability,anti-tumor,and neurotroph

3、ic activities.Recent studies have shown that PEDF is a metabolic regulatory protein that plays a casual role in glucose and lipid metabolism.This review focus on researches which regard PEDF as the causes of insulin resistance,describes the extensive contacts between PEDF and metabolic diseases,and

4、summarises the probable mechanisms adopted by PEDF to induce insulin resistance.Key words: PEDF; metabolism;insulin resistance;mechanisms:1 PEDF簡(jiǎn)介色素上皮細(xì)胞衍生因子（PEDF）是在人視網(wǎng)膜色素上皮細(xì)胞的分泌物發(fā)現(xiàn)并純化的50-KDa糖蛋白。該分泌性蛋白為非抑制功能的絲氨酸超家族的一員，在人體廣泛分布。最初認(rèn)為PEDF是一種生長(zhǎng)因子，能夠誘導(dǎo)神經(jīng)元的分化。直到1999年，人們才逐漸發(fā)現(xiàn)PEDF具有十分豐富的生理活性，包括抗血管新生1，抗腫瘤2-7，降

5、低血管通透性8，以及神經(jīng)營(yíng)養(yǎng)活性9。2 PEDF的生理結(jié)構(gòu)人類的PEDF是由418個(gè)氨基酸編碼的多肽，編碼基因位于第17號(hào)染色體短臂末端。除了1-35殘基，大多數(shù)的氨基酸殘基在N-端形成了二級(jí)結(jié)構(gòu)，并具有10個(gè)螺旋，3個(gè)片層的三級(jí)結(jié)構(gòu)。PEDF具有絲氨酸超家族典型的三維結(jié)構(gòu)活性中心螺旋（RCL）。RCL與多種類型的蛋白分泌抑制相關(guān)10。一項(xiàng)對(duì)中國(guó)倉(cāng)鼠卵巢細(xì)胞的研究顯示，若在C-端尾部對(duì)PEDF截?cái)啵瑒t會(huì)導(dǎo)致PEDF分泌減少。另外，RCL的活性部位P1與靶蛋白酶特異性結(jié)合后會(huì)導(dǎo)致其構(gòu)象改變，這種構(gòu)象改變能夠增加PEDF的穩(wěn)定性。PEDF可以通過多種方式抑制血管新生：抑制內(nèi)皮細(xì)胞遷移11，誘導(dǎo)內(nèi)皮

6、細(xì)胞凋亡12，抑制血管內(nèi)皮生長(zhǎng)因子（VEGF）的表達(dá)13等。盡管具體的機(jī)制尚未完全闡明，但已經(jīng)有相關(guān)研究表明PEDF的一些結(jié)構(gòu)域參與了該功能。其中PEDF的膠原蛋白I結(jié)合域在抗血管新生中起到了重要的作用14-15。該結(jié)合域突變會(huì)導(dǎo)致其抗血管新生活性消失。PEDF擁有其他絲氨酸超家族成員沒有的HA結(jié)合域。有研究報(bào)道，該HA結(jié)合域與細(xì)胞凋亡有關(guān)16-17，能夠通過激活caspase-8、caspase-3細(xì)胞通路、ADP-核糖聚合酶的活性導(dǎo)致腫瘤細(xì)胞凋亡。甘油三酯水解酶（ATGL）是位于質(zhì)膜表面的具有磷脂酶活性的跨膜蛋白。當(dāng)PEDF與游離脂質(zhì)結(jié)合時(shí)，ATGL就能夠作為PEDF的受體被激活18。67

7、-KDa層黏連蛋白受體（67LR）是PEDF在內(nèi)皮細(xì)胞的受體，定位在漿膜上，參與內(nèi)皮細(xì)胞的凋亡，抑制內(nèi)皮細(xì)胞的遷移，抑制血管新生19。PEDF通過與這些受體結(jié)合，激活對(duì)應(yīng)的細(xì)胞通路，從而發(fā)揮其生理功能。3 PEDF與胰島素抵抗目前有多項(xiàng)研究表明PEDF與IR有密切關(guān)系。但是PEDF究竟是會(huì)導(dǎo)致IR，還是改善IR尚存爭(zhēng)議。Yamagishi等人研究了PEDF與糖基化終末產(chǎn)物（AGE）的相關(guān)性。研究顯示PEDF能夠抑制Rac-1的活性，從而抑制AGE引起的肝細(xì)胞IRS-1酪氨酸磷酸化降低，還能夠阻斷JNK、IKB激酶依賴IRS-1絲氨酸磷酸化20。PEDF會(huì)阻斷AGE誘導(dǎo)的活性氧（ROS）、C-反

8、應(yīng)蛋白（CRP）的產(chǎn)生，從而起到抗炎癥、抗氧化應(yīng)激的作用21,22。因此，PEDF可改善AGE引起的肝細(xì)胞IR。Crowe等人的研究結(jié)果卻與之相反。小鼠短期注射PEDF會(huì)導(dǎo)致ERK、JNK磷酸化增加，胰島素信號(hào)通路中IRS1、AKT活性磷酸化位點(diǎn)的磷酸化減少23。因此PEDF會(huì)誘導(dǎo)產(chǎn)生IR。圖1：PEDF與代謝性疾病的廣泛聯(lián)系本文則綜述了支持PEDF引起IR的相關(guān)研究進(jìn)展。4 PEDF與代謝性疾病PEDF具有多能性，在不同的組織細(xì)胞中表現(xiàn)出不同的功能24。如：PEDF在血管抑制信號(hào)的作用下發(fā)揮了有效的抗炎癥作用25，在代謝系統(tǒng)中卻起到了致炎癥的作用26。PEDF既能夠調(diào)節(jié)-catenin介導(dǎo)的

9、經(jīng)典的Wnt信號(hào)通路，也能夠調(diào)節(jié)JNK介導(dǎo)的非經(jīng)典的Wnt信號(hào)通路。這提示PEDF引起的代謝炎癥可能與Wnt信號(hào)通路、TCF7L2一起誘導(dǎo)了II-型糖尿病的發(fā)生27。在多種代謝性疾病中（見圖1），PEDF的循環(huán)水平都會(huì)升高。Nakamura等人的研究表明，在II-型糖尿病人的血清中，中心性肥胖相關(guān)因子（腰圍、甘油三酯、腫瘤壞死因子-）與PEDF呈獨(dú)立性密切相關(guān)28。另外PEDF還與空腹胰島素水平、HOMA-IR、BMI、脂肪量呈負(fù)相關(guān)。由此可以猜測(cè)，糖尿病人的血清中的PEDF可能來源于內(nèi)臟脂肪組織中的不成熟的脂肪細(xì)胞。除了肝細(xì)胞和脂肪細(xì)胞，肌細(xì)胞也是PEDF的來源之一 29。肝細(xì)胞PEDF基因

10、的表達(dá)與肥胖者PEDF的水平呈正相關(guān)，且與胰島素抵抗（IR）II-型糖尿病人的丙氨酸轉(zhuǎn)移酶、天冬氨酸轉(zhuǎn)移酶的水平（代表肝功能）呈負(fù)相關(guān)。這表明，PEDF與IR相關(guān)，且肝臟是PEDF的主要來源30。PEDF與脂肪形成密切相關(guān)。最近的研究表明，PEDF可能促成脂肪組織的形成，促成IR和代謝功能紊亂31。Crowe32等人給予正常小鼠PEDF注射，用高胰島素-正葡萄糖鉗夾技術(shù)，檢測(cè)到胰島素敏感性降低，且若降低PEDF量，胰島素敏感性會(huì)有所回升。但是PEDF引起IR的機(jī)制暫不清楚。對(duì)嚙齒類動(dòng)物喂食PEDF引起IR的同時(shí)，血清中的TNF以及其他的細(xì)胞因子水平會(huì)有所上升。人體TNF輸液會(huì)導(dǎo)致機(jī)體葡萄糖攝入

11、功能損害，因此TNF可能是PEDF引起IR的下游調(diào)節(jié)分子。（見圖2）表1：目前研究中顯示的PEDF參與的代謝l 代謝紊亂時(shí)PEDF水平升高l 與心臟代謝危險(xiǎn)因子呈正相關(guān)l 是炎性疾病的藥物作用靶點(diǎn)l 與胰島素抵抗直接相關(guān)，PEDF減少會(huì)恢復(fù)胰島素敏感性l 提高ATGL介導(dǎo)的脂肪分解活性，導(dǎo)致游離脂肪酸增多l(xiāng) 還可能導(dǎo)致線粒體功能障礙一項(xiàng)臨床研究顯示，胰島素治療后的II-型糖尿病人血清中PEDF水平下降了15%。胰島素通過抑制11-羥基類固醇脫氫酶1（11-HSD1）的表達(dá)抑制了PEDF的分泌。而且在胰島素治療后，不僅僅在血清中，脂肪組織中的PEDF水平也會(huì)下降。Yabe33等人發(fā)現(xiàn)腫瘤壞死因子

12、-（TNF-）能夠通過激活NF-B，從而降低脂肪組織中PEDF含量。代謝綜合癥病人34，以及多囊卵巢?。≒COS）的病人血清中PEDF水平較高，而且與IR相關(guān)35。然而，最新的研究發(fā)現(xiàn)PCOS的病人PEDF的水平并沒有上升，反而與高血壓和血脂異常呈負(fù)相關(guān)36。PCOS病人的PEDF水平與CRP密切相關(guān)，暗示PEDF與PCOS病人慢性炎癥的發(fā)生有一定的聯(lián)系37。旁分泌PEDFATGL脂毒性線粒體功能障礙炎癥表現(xiàn)FFAs增多-胞內(nèi)脂沉積活性氧細(xì)胞因子、趨化因子增多FFAFFATLR4PKCsp38 MAPKJNK、IKKERK1/2IRS1/2IRS1/2P-SerIRS降解酪氨酸磷酸化抑制PI3

13、-激酶抑制自分泌胰島素抵抗PEDF的濃度與胰島素敏感性以及代謝活性也呈負(fù)相關(guān)38。表1總結(jié)了目前研究中顯示的PEDF參與的代謝。圖2：PEDF引起胰島素抵抗的可能機(jī)制5 PEDF引起胰島素抵抗的可能機(jī)制5.1 影響脂代謝阻斷胰島素信號(hào)轉(zhuǎn)導(dǎo)通路PEDF與脂肪的分解有關(guān)，能夠使游離脂肪酸（FFAs）增多。增多的FFAs會(huì)抑制磷脂酰肌醇3-激酶（PI3K）的激活，還會(huì)導(dǎo)致異位的脂沉積，這兩者均會(huì)阻斷胰島素信號(hào)轉(zhuǎn)導(dǎo)通路39。另外，胞內(nèi)的脂質(zhì)積累能夠激活PKC-,的活性。Yu等人發(fā)現(xiàn)，PKC的活性提高會(huì)伴隨著胰島素受體底物（IRS）的酪氨酸磷酸化以及葡萄糖轉(zhuǎn)移的降低。PKCs還能夠激活核因子抑制子IK、

14、JNKs40。一項(xiàng)研究胰島素與其靶器官的實(shí)驗(yàn)顯示，PEDF與JNK、IKK和ERK1/2的激活有關(guān)。JNK能夠磷酸化IRS-1中絲氨酸或蘇氨酸殘基，這種磷酸化作用會(huì)干擾胰島素受體與IRS-1的作用，從而阻止IRS-1的酪氨酸磷酸化41。IK與IRS-1組成復(fù)合物，與TNF介導(dǎo)的IR有關(guān)42。ERK1/2也可能是PEDF的作用靶點(diǎn)43，能夠引起IRS-1的絲氨酸磷酸化，抑制酪氨酸磷酸化，減弱胰島素信號(hào)轉(zhuǎn)導(dǎo)44。5.2 引起線粒體功能障礙PEDF能夠抑制脂肪酸氧化，從而形成一種“脂毒性”的環(huán)境。Gao等人的研究表明，F(xiàn)FAs能夠引起線粒體功能障礙45。PEDF能夠抑制與脂肪酸氧化和線粒體生成，還刺

15、激ATGL生成脂肪酸配體，從而激活過氧化體增殖物激活型受體（PPARs），增加線粒體的脂肪酸氧化46。功能紊亂的線粒體能夠生成ROS，導(dǎo)致胰島素抵抗。在胰島素抵抗的周緣組織中（如骨骼肌、肝臟、脂肪），線粒體數(shù)量降低、形態(tài)和功能異常。線粒體功能異常已經(jīng)被證實(shí)是引起IR的機(jī)制。PEDF引起的線粒體功能異常會(huì)阻礙胰島素信號(hào)轉(zhuǎn)導(dǎo)，還有損害線粒體生成。5.3 引起代謝炎癥代謝紊亂也被認(rèn)為是一種長(zhǎng)期低水平的炎癥狀態(tài)。PEDF通過直接或間接地方式引起代謝炎癥。（圖2）PEDF對(duì)炎癥級(jí)聯(lián)反應(yīng)的起始和維持有重要作用。PEDF引起的FFAs增多，會(huì)激活Toll樣受體介導(dǎo)的炎癥信號(hào)，從而激活I(lǐng)K和JNK。于是多種細(xì)

16、胞因子被激活，包括TNF、IL-1、IL-647。PEDF還可以激活p38細(xì)胞絲裂原蛋白激酶（MAPK）。在人臍靜脈內(nèi)皮細(xì)胞（HUVECs）實(shí)驗(yàn)中48，PEDF呈劑量依賴的增加p38和JNK的磷酸化，降低AKT活性。AKT活性的降低可以激活MAPK249。MAPK2的激活，又可以激活p38。因此PEDF可以引發(fā)，維持，并推進(jìn)激酶介導(dǎo)的絲氨酸/蘇氨酸磷酸化級(jí)聯(lián)反應(yīng)，抑制胰島素在外周組織的信號(hào)轉(zhuǎn)導(dǎo)。（表2）表2：PEDF引起IR的可能的病理過程可能的病因可能的機(jī)制發(fā)病介質(zhì)下游介質(zhì)結(jié)果PEDF炎癥細(xì)胞因子:TNFIL-1IL-6MCP-1P38 MAPK、JNK、IKK、ERK 1/2PKCsIRS

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