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脂聯(lián)素對(duì)肝臟糖脂代謝調(diào)節(jié)作用的研究進(jìn)展

2015-04-08 23:03李婷王安平母義明
生物技術(shù)通訊 2015年5期
關(guān)鍵詞:神經(jīng)酰胺脂聯(lián)素抵抗

李婷,王安平,母義明

解放軍總醫(yī)院 內(nèi)分泌科,北京 100853

自1995 年被首次發(fā)現(xiàn)以來,脂聯(lián)素的相關(guān)研究極大地改變了我們對(duì)脂肪組織的認(rèn)識(shí),提升了把脂肪組織作為一個(gè)內(nèi)分泌器官看待的重要性[1-2]。作為脂肪分泌的一種30 kD 大小的C1q 相關(guān)蛋白,脂聯(lián)素最初被命名為Acrp30。脂聯(lián)素由脂肪細(xì)胞特異性分泌,它對(duì)外周組織有很強(qiáng)的胰島素增敏作用,以及降低葡萄糖和促進(jìn)脂質(zhì)分解的功能。盡管脂聯(lián)素受體(AdipoR)最初被描述為骨骼肌特異性表達(dá)的AdipoR1和肝臟特異性表達(dá)的AdipoR2[3],但受體相對(duì)而言還是無處不在的。

紅外標(biāo)記示蹤研究揭示了脂聯(lián)素在肝臟、心臟、腎臟的作用靶點(diǎn),可視化免疫熒光技術(shù)發(fā)現(xiàn)內(nèi)分泌胰腺有全長(zhǎng)脂聯(lián)素的結(jié)合位點(diǎn)[4-5]。脂聯(lián)素是指示代謝健康的杰出臨床標(biāo)志物。觀察到肥胖病人循環(huán)內(nèi)脂聯(lián)素水平降低的同時(shí),為了研究脂聯(lián)素在中樞及外周代謝平衡中的作用,大量臨床前模型已經(jīng)建立起來[6-9]。在這里,我們特別針對(duì)脂聯(lián)素調(diào)節(jié)肝臟糖脂代謝的作用進(jìn)行闡述。

脂聯(lián)素在循環(huán)中有3 種存在形式,即三聚體、低分子量多聚體和高分子量多聚體。循環(huán)中的脂聯(lián)素水平與肥胖呈負(fù)相關(guān),作為炎癥介質(zhì)影響脂聯(lián)素的生產(chǎn)和釋放。一些抵抗糖尿病的治療能夠改善循環(huán)中脂聯(lián)素的水平,包括噻唑烷二酮類藥物(TZDPPARγ 激動(dòng)劑)、堿性成纖維細(xì)胞生長(zhǎng)因子21(FGF21)、抗炎化合物,并能降低體重。值得注意的是,TZD[10-11]或FGF21[12-13]的降血糖作用必須依靠脂聯(lián)素的表達(dá)。脂聯(lián)素中的高分子量多聚體是臨床上觀察TZD 藥效的最佳分子標(biāo)記物[14],同時(shí)在應(yīng)用FGF21 的治療中能顯著增加[15]。此外,飲食和鍛煉,作為治療糖尿病的一線方案,都可以獨(dú)立提高循環(huán)中的脂聯(lián)素水平[16-17]。鍛煉還可通過上調(diào)AdipoR 表達(dá)來上調(diào)脂聯(lián)素作用[18]。總的來說,文獻(xiàn)表明針對(duì)脂聯(lián)素的生產(chǎn)或脂聯(lián)素信號(hào)轉(zhuǎn)導(dǎo)來預(yù)防或治療肥胖相關(guān)的代謝紊亂很有發(fā)展?jié)摿Φ摹?/p>

1 脂聯(lián)素改善脂質(zhì)代謝

肝臟在碳水化合物、脂質(zhì)、氨基酸代謝和必需蛋白質(zhì)合成過程中扮演重用角色。在慢性營(yíng)養(yǎng)過剩的情況下,肝臟將出現(xiàn)過量的脂質(zhì)沉積(脂肪變性)和胰島素抵抗。肝臟疾病可由一系列因素引起,包括遺傳因素、異味的脂質(zhì)沉積和病毒感染。脂肪肝是發(fā)生頻率最高的慢性肝臟疾病之一。根據(jù)酒精對(duì)疾病的貢獻(xiàn)程度可將脂肪肝分為2 類,即非酒精性脂肪肝(NAFLD)和酒精性脂肪肝(ALD)。NAFLD 在工業(yè)性國(guó)家影響著約三分之一的人口,其特點(diǎn)是過量的甘油三酯沉積,肝細(xì)胞內(nèi)有可見的脂肪微粒[19]。

脂聯(lián)素能給肝臟提供很多保護(hù),通過改善脂聯(lián)素信號(hào)通路能改善相關(guān)代謝。臨床數(shù)據(jù)提示NAFLD 的發(fā)展與胰島素抵抗相關(guān),大多數(shù)病人都患有超重、肥胖、血脂障礙和高血壓。即使在正常胰島素耐量的正常體重患者中,NAFLD 與胰島素抵抗、高胰島素血癥之間仍然有聯(lián)系[20]。然而,脂肪變性和胰島素抵抗之間的因果聯(lián)系仍然有爭(zhēng)議,特別是在一些有遺傳傾向的人群中。肥胖相關(guān)的脂聯(lián)素下調(diào)可能導(dǎo)致胰島素抵抗和糖尿病發(fā)生。臨床上,脂聯(lián)素已被證明與肥胖及NAFLD 呈負(fù)相關(guān),現(xiàn)在大量針對(duì)脂肪肝的治療都能提高脂聯(lián)素的水平。除了其強(qiáng)大的胰島素增敏作用,脂聯(lián)素還能降低肝葡萄糖生產(chǎn),增加肝臟脂肪酸氧化,降低炎癥,促進(jìn)肝細(xì)胞的存活和減少纖維化。毫不奇怪,NAFLD 患者顯著降低血漿脂聯(lián)素水平與胰島素抵抗[21-22]。

2 脂聯(lián)素抵制肝細(xì)胞脂肪變性

膳食中的脂質(zhì)代謝主要在腸道,在那里被分解合成甘油三酯(TG),然后重新包裝成乳糜微粒膽固醇和蛋白質(zhì)。乳糜微粒是小腸分泌的脂蛋白顆粒,它的功能是把外源性脂質(zhì)從血液中運(yùn)輸?shù)礁闻K,在肝臟可以被重新包裝成脂蛋白顆粒。

作為脂蛋白到達(dá)靶組織,TG 被脂蛋白脂肪酶水解生成甘油和游離脂肪酸(FFA),然后作為能量來源進(jìn)入細(xì)胞,或者作為細(xì)胞膜脂質(zhì)合成的物質(zhì)。FFA 通過反酯化再形成TG,從而使得多余的脂質(zhì)在靶組織沉積。當(dāng)機(jī)體需要能量時(shí),存儲(chǔ)的TG可以通過脂解作用再分解成FFA。

肝脂肪變性的特點(diǎn)是TG積累,肝細(xì)胞中有脂滴沉積。對(duì)肝脂肪變性的臨床定義是TG含量>55 mg/g,>5%肝細(xì)胞可見脂滴[19]。外源性脂類導(dǎo)致的高循環(huán)FFA以及外周組織對(duì)肝臟的信號(hào)均可增加脂質(zhì)的攝取,減少極低密度脂蛋白。肝細(xì)胞脂質(zhì)過載可損害線粒體功能[23]。

臨床前模型提示我們脂聯(lián)素在維護(hù)肝臟脂質(zhì)代謝中的作用。脂聯(lián)素基因敲除小鼠高脂飼養(yǎng)48 周后[24],肝脂肪性肝炎和腺瘤高發(fā),但對(duì)短期的飲食干預(yù)[25-26]沒有明顯反應(yīng)。在瘦素敲除小鼠體內(nèi)讓脂聯(lián)素基因沉默,將進(jìn)一步加劇TG 的積累[12]。相反,脂聯(lián)素過表達(dá)模型能防治TG的沉積,并且降低有害的脂質(zhì)代謝產(chǎn)物甘油二酯或神經(jīng)酰胺[9,27]。類似效果同樣出現(xiàn)在其他高脂聯(lián)素血癥的轉(zhuǎn)基因小鼠,繼發(fā)脂肪細(xì)胞線粒體的功能變化,它們發(fā)生難治性的TG、甘油二酯或神經(jīng)酰胺的積累[28]。在嚙齒類動(dòng)物中有關(guān)優(yōu)化脂質(zhì)代謝的試驗(yàn)結(jié)果顯示,重組脂聯(lián)素的干預(yù)能增加肌肉和肝臟中的脂質(zhì)清除和脂肪酸氧化[29-30]。一些研究團(tuán)隊(duì)也證明在嚙齒類動(dòng)物的慢性乙醇實(shí)驗(yàn)?zāi)芙档脱h(huán)脂聯(lián)素濃度[30-32]。腺病毒介導(dǎo)的脂聯(lián)素過表達(dá)能減輕肝腫大、肝臟脂肪變性和慢性乙醇實(shí)驗(yàn)中小鼠的肝損失[30]。

脂聯(lián)素通過減少FFA 流入肝臟、增加FFA 氧化和線粒體生物合成來抑制肝臟脂肪變性[24]。AdipoR基因調(diào)控的研究表明類似趨勢(shì),脂聯(lián)素基因單核苷酸多態(tài)性受體是與肝TG 積累甚至肝硬化風(fēng)險(xiǎn)顯著相關(guān)的[33-34]。在小鼠肝脂肪變性模型中也觀察到AdipoR2 表達(dá)的減少[35]。AdipoR 的表達(dá)從反面表明了脂聯(lián)素信號(hào)轉(zhuǎn)導(dǎo)和肝臟脂肪變性之間潛在的因果關(guān)系[36]。腺病毒介導(dǎo)的任何一個(gè)AdipoR的過度表達(dá)都足以刺激脂質(zhì)氧化、減少肝臟TG 含量[37]。相反,缺乏AdipoR 的小鼠顯示肝臟TG 蓄積增強(qiáng)??傊?,低血漿脂聯(lián)素水平和肝臟低AdipoR2 水平的聯(lián)合效應(yīng)可能會(huì)促進(jìn)肝臟發(fā)生脂肪變性。

在ALD 情況下,慢性乙醇暴露被認(rèn)為是導(dǎo)致肝臟脂肪合成增強(qiáng)的原因,抑制轉(zhuǎn)錄因子如AMPK、SIRT1、PGC-1α、PPARα和SREBP-1 等會(huì)導(dǎo)致脂肪酸氧化受損[31]。脂聯(lián)素與其受體結(jié)合能激活類似途徑,AdipoR 最初被證實(shí)能上調(diào)AMPK 和PPARα[38]。反過來,AMPK 在通過乙酰輔酶A 羧化酶調(diào)節(jié)脂肪酸氧化速率,隨后肉堿棕櫚酰轉(zhuǎn)移酶-1(CPT-1)的激活促進(jìn)線粒體吸收脂肪酸(增加β氧化)這一過程中起關(guān)鍵作用。此外,AMPK 和SIRT1 可提高PGC-1α并降低其乙?;?,促進(jìn)線粒體生物合成,從而增強(qiáng)脂質(zhì)氧化能力[39]。脂聯(lián)素的其他抗脂毒性似乎是通過調(diào)節(jié)PPARα的轉(zhuǎn)錄產(chǎn)生的,包括脂質(zhì)合成酶減少、CPT-1增加、高密度脂蛋白分泌與合成增加[40]。

3 脂聯(lián)素減少神經(jīng)酰胺在肝臟內(nèi)的積累

神經(jīng)酰胺是由鞘氨醇骨干脂類和脂肪酸組成的脂質(zhì)家族。首先,絲氨酸和棕櫚酰CoA 形成18 碳骨架,然后通過一系列酶促反應(yīng)形成神經(jīng)酰胺。神經(jīng)酰胺可通過抑制胰島素中央信號(hào)Akt 來降低胰島素的作用[41],因此,細(xì)胞內(nèi)高水平的神經(jīng)酰胺與營(yíng)養(yǎng)吸收減少、胰島素敏感性下降和細(xì)胞凋亡增加有關(guān)。神經(jīng)酰胺經(jīng)神經(jīng)酰胺酶發(fā)生去乙?;尫懦銮拾贝己虵FA。一旦神經(jīng)酰胺轉(zhuǎn)化為鞘氨醇,就會(huì)被鞘氨醇激酶磷酸化生成1-磷酸鞘氨醇(S1P)[5,41]。已知S1P 與神經(jīng)酰胺的作用相反,它可以促進(jìn)細(xì)胞的存活,改善胰島素敏感性,減少炎癥。因此,神經(jīng)酰胺和S1P 的相對(duì)比例對(duì)于細(xì)胞存活及其胰島素敏感性是至關(guān)重要的。因而,在維持代謝平衡的過程中,調(diào)節(jié)神經(jīng)酰胺的代謝是必不可少的。顯然,脂聯(lián)素與S1P 在改善代謝方面的效應(yīng)有很大一部分重疊,因此提出了一種可能性:脂聯(lián)素可以通過對(duì)神經(jīng)酰胺的軸的影響發(fā)揮其活性。

神經(jīng)酰胺的代謝調(diào)控與脂肪攝入量的增加、炎癥上調(diào)及脂聯(lián)素下調(diào)都密切相關(guān)[42]。脂質(zhì)代謝產(chǎn)物的積累會(huì)出現(xiàn)由脂聯(lián)素誘導(dǎo)的脂質(zhì)過氧化損傷[43]。用不同的脂聯(lián)素小鼠模型實(shí)驗(yàn),發(fā)現(xiàn)脂聯(lián)素的基因劑量與高脂飲食誘導(dǎo)后肝臟內(nèi)神經(jīng)酰胺含量呈負(fù)相關(guān)[5]。過表達(dá)任何一種AdipoR 異構(gòu)體均能減少肝神經(jīng)酰胺的積累和提高神經(jīng)酰胺酶的活性。在細(xì)胞培養(yǎng)實(shí)驗(yàn)中,利用基因上調(diào)或下調(diào)AdipoR,進(jìn)一步闡明脂聯(lián)素通過其受體介導(dǎo)誘導(dǎo)神經(jīng)酰胺酶活性的作用。研究表明,這類受體與神經(jīng)酰胺活性的不同系統(tǒng)聯(lián)系是支持上述觀點(diǎn)的[44-45]。這些受體傳導(dǎo)的神經(jīng)酰胺酶活性可以被脂聯(lián)素進(jìn)一步提高,在下調(diào)神經(jīng)酰胺的同時(shí)增加S1P。總的來說,這些數(shù)據(jù)顯示,AdipoR1和2的活化上調(diào)了神經(jīng)酰胺酶活性,最終促進(jìn)S1P 產(chǎn)生[5,47]。在此過程中產(chǎn)生的鞘氨醇和S1P 可能足以激活PPARα和AMPK 這些脂聯(lián)素信號(hào)下游介質(zhì)。S1P 足以誘導(dǎo)AMPK 磷酸化[5],和鞘氨醇已被報(bào)道為PPARα的配體[46]。在脂質(zhì)氧化時(shí),神經(jīng)酰胺可損傷脂質(zhì)氧化,通過激活蛋白磷酸酶2A 促進(jìn)AMPK 失活[47-48]。在體外肝細(xì)胞中發(fā)現(xiàn)酒精依賴神經(jīng)酰胺性下調(diào)AMPK 活性,可能是脂肪肝疾病相關(guān)的病因[47]。此外,神經(jīng)酰胺在ALD 的嚙齒類動(dòng)物模型中持續(xù)升高[49-52],并且可以通過丙咪嗪、伏馬菌素B1、神經(jīng)磷脂酶抑制劑或直接從源頭針對(duì)性降低神經(jīng)酰胺的合成,使神經(jīng)酰胺下調(diào)[47]。

局部或全身上調(diào)S1P 可表達(dá)脂聯(lián)素的抗凋亡作用,因此S1P 足以概括脂聯(lián)素在心肌細(xì)胞和胰島B細(xì)胞的保護(hù)作用。換言之,脂聯(lián)素能通過AdipoR 介導(dǎo)的增加神經(jīng)酰胺酶活性而降低神經(jīng)酰胺的含量,防止細(xì)胞凋亡,即驅(qū)動(dòng)神經(jīng)酰胺/S1P 變阻器對(duì)S1P介導(dǎo)的存活和增殖。組織都處于死亡與生存、增殖與更新的不斷平衡之間,對(duì)于幾個(gè)特定組織而言,脂聯(lián)素對(duì)細(xì)胞生存和自我更新起關(guān)鍵作用[5,53]。脂聯(lián)素敲除小鼠行肝部分切除術(shù),肝臟再生能力受損[54],S1P生產(chǎn)對(duì)恢復(fù)中的促有絲分裂行為至關(guān)重要[55]。

4 脂聯(lián)素能抵抗炎癥反應(yīng)

究竟是什么推動(dòng)了從單純性脂肪肝到脂肪性肝炎的過渡仍不清楚,有可能是由過渡脂毒性所連接的[56]。脂毒性描述的是脂質(zhì)沉積于脂肪組織以外的組織所產(chǎn)生的后果——細(xì)胞功能障礙或凋亡[57-58]。當(dāng)肝細(xì)胞內(nèi)TG的存儲(chǔ)超過上限值,積累的脂質(zhì)會(huì)損害細(xì)胞的功能并促進(jìn)細(xì)胞凋亡。隨著功能性肝細(xì)胞的損失和凋亡,炎性細(xì)胞因子和各種應(yīng)激信號(hào)也被釋放,因此在細(xì)胞周圍創(chuàng)造了一個(gè)毒性的環(huán)境。這種毒性可以觸發(fā)細(xì)胞防御和修復(fù)機(jī)制,包括肝纖維化和細(xì)胞凋亡[59]。

Toll 樣受體4(TLR4)可以作為一個(gè)異常脂質(zhì)穩(wěn)態(tài)后果而被激活。研究表明,飽和脂肪酸可以間接激活TLR4信號(hào),啟動(dòng)炎癥反應(yīng)和神經(jīng)酰胺合成酶的生產(chǎn)[60]。直接和間接激活TLR4 均能激活下游NFκB 信號(hào)通路。這一活化過程會(huì)增加促炎性細(xì)胞因子的生產(chǎn)和上調(diào)神經(jīng)酰胺[61]。神經(jīng)酰胺本身也通過激活I(lǐng)KKb 誘導(dǎo)劑和Jun 氨基末端激酶(JNK)參與炎癥通路[62]。在急性炎癥反應(yīng)中,促炎性細(xì)胞因子有一個(gè)短暫的半衰期,從而限制炎癥反應(yīng)持續(xù)時(shí)間。為了嚴(yán)格控制炎癥反應(yīng),抗炎性細(xì)胞因子能夠?qū)姑庖呒せ詈鸵种拼傺仔约?xì)胞因子的激活。這種調(diào)節(jié)伴隨著巨噬細(xì)胞介導(dǎo)的死細(xì)胞的去除,從而終止炎癥信號(hào)源[63]。

有報(bào)道稱,用巨噬細(xì)胞樣細(xì)胞系,球形脂聯(lián)素可以使TLR4 介導(dǎo)的信號(hào)通路正?;痆64]。一組采用原代Kupffer 細(xì)胞的實(shí)驗(yàn)也表明脂聯(lián)素具有脂多糖脫敏和抗炎作用[65]??偟膩碚f,脂聯(lián)素通過激活NFκB 信號(hào)、減少促炎反應(yīng)、減少組織中神經(jīng)酰胺的積累來發(fā)揮抗炎作用。

5 脂聯(lián)素增加肝臟胰島素敏感性并減少肝臟葡萄糖的產(chǎn)生

有幾個(gè)實(shí)驗(yàn)室研究了脂聯(lián)素對(duì)糖脂代謝的影響。Berg等報(bào)道,在野生型小鼠和糖尿病小鼠中,分別用2 倍和5 倍正常循環(huán)水平的脂聯(lián)素可以降低血糖[66]。在高脂飼料條件下,脂聯(lián)素基因敲除小鼠出現(xiàn)葡萄糖耐量抵抗和嚴(yán)重的肝胰島素抵抗,而不是肌肉胰島素抵抗[10]。在胰島素鉗夾研究中,發(fā)現(xiàn)注射純化的重組脂聯(lián)素可改善胰島素的作用[5,66]。不論是WT 還是ob/ob 背景的小鼠,葡萄糖鉗夾實(shí)驗(yàn)中脂聯(lián)素影響體內(nèi)的葡萄糖代謝歸因于葡萄糖生產(chǎn)速度降低65%。脂聯(lián)素沒有影響葡萄糖攝取、糖酵解率或糖原合成,相反,在循環(huán)脂聯(lián)素水平急性升高時(shí)能降低肝葡萄糖生產(chǎn),但對(duì)于肌肉葡萄糖的攝取沒有影響。這進(jìn)一步證明肝臟糖異生酶如磷酸烯醇式丙酮酸羧激酶和葡萄糖-6-磷酸酶的表達(dá),脂聯(lián)素輸液能使其mRNA 降低50%以上,表明循環(huán)中脂聯(lián)素水平的溫和上升可以抑制肝臟糖異生酶的表達(dá)和內(nèi)源性葡萄糖生成率。然而,這些降血糖作用與觀察到的胰島素上升不一致,暗示它的影響主要是胰島素靈敏度。與這些嚙齒類動(dòng)物的研究一致,空腹脂聯(lián)素水平與人類胰島素敏感性強(qiáng)烈相關(guān)[67]。

脂聯(lián)素增強(qiáng)胰島素敏感性的機(jī)制長(zhǎng)期被認(rèn)為是受體介導(dǎo)的,激活A(yù)MPK 通路,刺激葡萄糖的利用率和脂肪酸氧化[10,68]。然而,最近的報(bào)道也揭示了不依賴于AMPK 的機(jī)制[5,69]。誘導(dǎo)下調(diào)肝臟中的AMPK/LKB1 信號(hào)通路,脂聯(lián)素仍能有效改善葡萄糖穩(wěn)態(tài)。受體介導(dǎo)的神經(jīng)酰胺酶活性是脂聯(lián)素在肝臟和其他組織產(chǎn)生影響的一個(gè)主要信號(hào)機(jī)制。雖然神經(jīng)酰胺酶能激活A(yù)MPK,但AMPK 信號(hào)通路并不是脂聯(lián)素促進(jìn)神經(jīng)酰胺酶激活、下調(diào)神經(jīng)酰胺所必需的[5]。Miller等認(rèn)為,在高胰島素-正常血糖鉗夾技術(shù)中,即使缺乏LKB1/AMPK信號(hào)通路的情況下,脂聯(lián)素仍然可以減少糖異生基因的表達(dá)和促進(jìn)胰島素誘導(dǎo)的肝葡萄糖釋放[69]。

暴露于過量循環(huán)飽和脂類[30,73]、糖皮質(zhì)激素[30,70]、膳食脂肪[71,72],或經(jīng)常過度消耗營(yíng)養(yǎng)物質(zhì)(由于瘦素缺乏),可增加肝神經(jīng)酰胺在動(dòng)物模型中的積累,這些與肝胰島素抵抗有關(guān)[5,12,30,73]。值得注意的是,靶向抑制神經(jīng)酰胺合成可使肝神經(jīng)酰胺正?;?,恢復(fù)胰島素在這些模型中抑制肝葡萄糖輸出的能力。脂聯(lián)素介導(dǎo)改善肝胰島素作用,所需時(shí)間與使ob/ob小鼠肝臟中神經(jīng)酰胺的水平正?;恢耓5]。雖然神經(jīng)酰胺可在肥胖的胰島素抵抗人群的肝臟中積累[50],在肝臟胰島素抵抗中,神經(jīng)酰胺的具體作用是作為標(biāo)志物還是胰島素抵抗的原因,仍存在爭(zhēng)論[74]。

流行病學(xué)研究表明脂聯(lián)素和胰島素敏感性有較強(qiáng)的相關(guān)性,兩者與肥胖緊密相關(guān)[75]。與胰島素抵抗相關(guān)的脂聯(lián)素及其受體的幾種遺傳多態(tài)性已確定。與鞘脂類有關(guān)的一個(gè)單核苷酸多態(tài)性,其生產(chǎn)需要飽和脂肪,AdipoR1 的多態(tài)性積極響應(yīng)了飽和脂肪酸引起的胰島素抵抗[76]。

上調(diào)循環(huán)中的脂聯(lián)素,與胰島素增敏劑的臨床療效密切相關(guān)。值得注意的是,PPARγ激動(dòng)劑TZD與脂聯(lián)素誘導(dǎo)密切相關(guān)。在臨床前模型中,脂聯(lián)素是低劑量TZD改善高血糖所必需的[10-11]。在人類中,TZD 誘導(dǎo)的改善糖質(zhì)新生的作用與循環(huán)脂聯(lián)素增加密切相關(guān)[77]。脂聯(lián)素的高分子量形式是TZD 藥物改善葡萄糖穩(wěn)態(tài)的最佳預(yù)測(cè)[78],脂聯(lián)素高分子量水平比總脂聯(lián)素水平能更好地反應(yīng)與胰島素敏感性的相關(guān)性[79]。另一個(gè)很有前途的胰島素增敏劑,F(xiàn)GF21,最近也作為潛在的可改善胰島素抵抗的治療藥物出現(xiàn)。FGF21 是PPARα(肝)或PPARγ(脂肪)的一個(gè)靶蛋白,它在嚙齒類動(dòng)物[80-81]和人類[15]都能增加血漿中的脂聯(lián)素含量,并且大部分抗糖尿病的作用是需要脂聯(lián)素來完成的[12-13]。

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