林志忠,葉志云,林圣彩,林舒勇

(廈門大學(xué)生命科學(xué)學(xué)院,福建 廈門 361102)

三磷酸腺苷(ATP)是幾乎所有細(xì)胞和有機(jī)體中最重要的能量載體,ATP水解成二磷酸腺苷(ADP)所釋放出的能量直接用于絕大多數(shù)生命活動,當(dāng)能量進(jìn)一步缺乏時(shí)ADP可再轉(zhuǎn)變?yōu)閱瘟姿嵯佘?AMP)以提供更多的能量;而當(dāng)能量充足時(shí),細(xì)胞又可將AMP和ADP 重新轉(zhuǎn)化成ATP從而將能量存儲起來．在正常情況下,大部分真核細(xì)胞中的ATP濃度始終維持在一個(gè)非常穩(wěn)定的水平,因此細(xì)胞中必然存在一個(gè)可以感知ATP、ADP和AMP水平變化的機(jī)制．

AMP激活的蛋白激酶(AMP-activated protein kinase,AMPK)目前已被公認(rèn)是有機(jī)體和細(xì)胞內(nèi)感應(yīng)能量水平并調(diào)節(jié)代謝穩(wěn)態(tài)的最重要分子．早期的研究發(fā)現(xiàn),向大鼠的肝臟勻漿中加入AMP或ADP,可以有效地抑制2種脂肪酸合成過程中的關(guān)鍵酶——3-羥基-3-甲基戊二酸單酰輔酶A還原酶(HMG-CoA reductase)和乙酰輔酶A羧化酶(acetyl-CoA carboxy-lase,ACC)的活力從而強(qiáng)烈地抑制肝臟的脂肪合成[1-3]．進(jìn)一步的研究表明,這一抑制作用實(shí)際上是由AMP引起的,且依賴于某個(gè)未知蛋白激酶的催化反應(yīng)[4]．為了找到這個(gè)未知的蛋白激酶,蘇格蘭鄧迪大學(xué)的Hardie實(shí)驗(yàn)室對大鼠肝臟勻漿進(jìn)行了分離和純化,并對能夠響應(yīng)AMP抑制ACC的組分進(jìn)行了近4年的細(xì)致分析,終于在1989年找到了一個(gè)由分子質(zhì)量分別為63,38和35 ku的3個(gè)亞基組成的蛋白,并根據(jù)該蛋白能被AMP激活的特性將其命名為AMPK[5]．

后來的研究表明,當(dāng)細(xì)胞內(nèi)處于能量缺乏狀態(tài)時(shí),AMPK被激活,進(jìn)而直接導(dǎo)致了多條信號通路的抑制或激活并引起一系列的生理變化(圖1),包括：促進(jìn)脂肪細(xì)胞中甘油三酯的水解[6]，促進(jìn)肝臟對血液中脂肪酸的攝取和氧化[7]，抑制脂肪酸和膽固醇的合成以及甘油三酯的形成[8-9],促進(jìn)肌肉中脂類氧化以及葡萄糖的攝取和分解[10-11]，抑制胰島β細(xì)胞分泌胰島素以及糖原的合成[12]，抑制蛋白質(zhì)的合成并促進(jìn)自噬作用[13-15]和酮體的生成[16]等．其中,抑制脂肪酸合成并促進(jìn)其氧化被認(rèn)為是AMPK最經(jīng)典的功能,主要是通過磷酸化并抑制其底物ACC的活力實(shí)現(xiàn)的,而ACC又是脂肪酸合成的關(guān)鍵酶[10]．這些作用的結(jié)果是增加體內(nèi)的產(chǎn)能代謝,減少體內(nèi)的耗能代謝,穩(wěn)定體內(nèi)能量水平，維持能量穩(wěn)態(tài),從而保證細(xì)胞的正常生命活動．由此可見,AMPK是機(jī)體內(nèi)最重要的能量穩(wěn)態(tài)調(diào)節(jié)者,它的功能和人類的生存與健康密切相關(guān)．

圖1　AMPK參與調(diào)控的許多重要細(xì)胞生物學(xué)過程Fig.1 Multiple important cellular biological processes regulated by AMPK

1　AMPK的結(jié)構(gòu)

AMPK是由α、β和γ 3個(gè)亞基構(gòu)成的一個(gè)異源三聚體．α亞基的N 端是AMPK催化活性的核心區(qū)域,包含一個(gè)保守的絲氨酸/蘇氨酸激酶結(jié)構(gòu)域(kinase domain,KD)、C端的β亞基相互作用結(jié)構(gòu)域(β-subunit interacting domain,β-SID)和與C端緊鄰的自抑制結(jié)構(gòu)域(autoinhibitory domain,AID),其中AID的作用是通過結(jié)合KD來抑制α亞基的激酶活性[17-18];β亞基包含一個(gè)中等碳水化合物的結(jié)合模塊(mid-molecule carbohydrate-binding module,CBM)和一段位于C末端的連接α和γ亞基的結(jié)合序列(α,γ subunit-binding sequence,SBS);γ亞基含有4個(gè)參與結(jié)合ATP、AMP等的胱硫醚β-合成酶(cystathionine-β-synthase,CBS)結(jié)構(gòu)域．當(dāng)AMP結(jié)合到γ亞基上的CBS結(jié)構(gòu)域時(shí)會引起該亞基發(fā)生變構(gòu),隨后影響AID的構(gòu)象,使α亞基上的蘇氨酸172(T172)位點(diǎn)暴露出來,導(dǎo)致該位點(diǎn)被AMPK的上游激酶磷酸化[18-22]；同時(shí)由于AMP的結(jié)合導(dǎo)致的構(gòu)象變化還可阻止該位點(diǎn)的去磷酸化,從而使AMPK保持較高的激活水平．相反地,ATP的結(jié)合則能夠抑制這一過程[23-24]．

在哺乳動物細(xì)胞中,AMPK的α和β亞基各包含2種不同的亞型(α1、α2和β1、β2),γ亞基包含3種不同的亞型(γ1、γ2和γ3),這些亞型均由不同的基因編碼表達(dá),它們可以組合成至少12種不同的AMPK三聚體[25-26]．研究發(fā)現(xiàn)這些亞型的表達(dá)具有組織特異性,γ2在人體的心肌細(xì)胞中高度表達(dá),而γ3則集中表達(dá)于快速抽動的骨骼肌細(xì)胞中;此外,在不同物種之間這些亞型的表達(dá)差異很大,如γ2在人的心肌細(xì)胞中高表達(dá),但在小鼠的心肌細(xì)胞中表達(dá)量卻很低,而在小鼠的腦組織和脂肪組織中又是高表達(dá)的[27-28]．因此,AMPK不同亞型之間的關(guān)聯(lián)性及其在不同物種、不同組織細(xì)胞中所發(fā)揮的功能還有待進(jìn)一步的深入研究．

2　AMPK的調(diào)控機(jī)制

如上所述,AMPK的激活依賴于其T172位點(diǎn)的磷酸化,目前已發(fā)現(xiàn)2種主要的上游激酶，分別為肝臟激酶B1(liver kinase B1,LKB1)和鈣離子/鈣調(diào)蛋白依賴蛋白激酶β(Ca2+/calmodulin-activated protein kinase β,CaMKKβ)[29-32]．LKB1是一個(gè)腫瘤抑制因子,自身處于持續(xù)激活的狀態(tài),當(dāng)組織缺氧、缺血或運(yùn)動導(dǎo)致細(xì)胞內(nèi)能量缺乏時(shí),細(xì)胞內(nèi)AMP/ATP比值上升,AMP與AMPK結(jié)合時(shí)后者的構(gòu)象發(fā)生改變,使得AMPK的T172位點(diǎn)暴露出來,從而使LKB1能夠?qū)υ撐稽c(diǎn)進(jìn)行磷酸化,并可使其活性上升100倍以上[29]；而CaMKKβ則需要在細(xì)胞內(nèi)鈣離子濃度升高時(shí)才能被激活，并進(jìn)而磷酸化AMPK[30，33]．另外,早期的研究表明ADP與AMPK結(jié)合亦可引發(fā)與AMP相同的效應(yīng)[34-35];但是較新的一項(xiàng)研究證明,只有當(dāng)AMP與AMPK結(jié)合后LKB1才對其T172位點(diǎn)進(jìn)行磷酸化,而ADP的結(jié)合只參與了抑制該位點(diǎn)的去磷酸化[22]．然而,這些發(fā)現(xiàn)大都基于體外的生化實(shí)驗(yàn),AMPK在體內(nèi)被激活的機(jī)制，以及AMP對AMPK磷酸化的具體作用長期以來一直不為人知．

2013年,本課題組率先揭開了AMPK在體內(nèi)被激活的“路線圖”，發(fā)現(xiàn)體軸發(fā)育抑制因子(axis inhibitor,AXIN)是LKB1激活A(yù)MPK所必需的，其中AXIN是一個(gè)多功能的構(gòu)架蛋白,參與調(diào)節(jié)許多信號通路,如Wnt、JNK和p53等,對細(xì)胞生長起重要的調(diào)控作用[36-40]．當(dāng)細(xì)胞在饑餓狀態(tài)下,由于AMP結(jié)合至AMPK后增強(qiáng)了后者對AXIN的親和力,而AXIN自身與LKB1有很強(qiáng)的相互作用，所以此時(shí)的AXIN起到了一個(gè)橋梁的作用,將AMPK和其上游激酶LKB1連接在一起,三者形成一個(gè)復(fù)合體,促進(jìn)了LKB1對AMPK的磷酸化激活,使得AMPK的活性升高[41](圖2)．以上研究成果完善了AMPK活性調(diào)控過程中的關(guān)鍵一環(huán),揭示了AMP促進(jìn)AMPK磷酸化的分子機(jī)制．

圖2　AXIN激活A(yù)MPK的機(jī)制[41]Fig.2 Mechanism of AMPK activation by AXIN[41]

引自參考文獻(xiàn)[42],經(jīng)修改．圖3　v-ATPase-Ragulator復(fù)合體調(diào)控AMPK和mTORC1活化切換的機(jī)制Fig.3 Mechanism of switch between AMPK and mTORC1 activation regulated by v-ATPase-Ragulator complex

隨后,本課題組又通過酵母雙雜交的方式找到了和AXIN相互作用的溶酶體相關(guān)膜蛋白LAMTOR1,并且證明該蛋白也是能量缺乏情況下AMPK激活所必需的[42]．LAMTOR1是一個(gè)錨定在溶酶體膜表面的蛋白復(fù)合體Ragulator的重要成員,在缺乏LAMTOR1的小鼠或細(xì)胞中,饑餓信號不能引起AMPK的激活．在能量充足的情況下,Ragulator通過其自身的鳥苷酸交換因子(guanine nucleotide exchange factor,GEF)激活鳥苷酸酶Rag,從而使哺乳動物雷帕霉素靶蛋白復(fù)合體1(mammalian target of rapamycin complex 1,mTORC1)遷移到溶酶體上并被激活,這時(shí)合成代謝途徑開啟(圖3(a))；而在能量不足的情況下,溶酶體上的能量感知者空泡型ATP酶(vacuolar-type ATPase,v-ATPase)發(fā)生變構(gòu),通過與其相互作用的Ragulator復(fù)合體共同促進(jìn)AXIN-LKB1遷移到溶酶體上并與Ragulator結(jié)合,最后在此激活A(yù)MPK，同時(shí)AXIN抑制了Ragulator的GEF活力,進(jìn)一步促進(jìn) mTORC1的解離,從而關(guān)閉合成代謝途徑,開啟分解代謝途徑(圖3(b))．

綜上,本課題組發(fā)現(xiàn)細(xì)胞內(nèi)由于葡萄糖缺乏所引起的AMPK激活是在溶酶體膜上進(jìn)行的,并且揭示了該過程所涉及的蛋白質(zhì)機(jī)器．這一發(fā)現(xiàn)不僅揭示了AMPK在體內(nèi)生理狀態(tài)下被激活的方式與過程,也解析了細(xì)胞在營養(yǎng)物質(zhì)缺乏的情況下調(diào)節(jié)合成代謝與分解代謝的切換機(jī)制．

此外,除了能量缺乏以外,AMPK還可以響應(yīng)多種藥物的刺激而被激活[43]．根據(jù)作用機(jī)制的不同可以將這些藥物分為以下3大類:1) 線粒體復(fù)合體抑制劑，通過抑制呼吸鏈來提高細(xì)胞內(nèi)AMP/ADP水平從而激活A(yù)MPK,常見的如二甲雙胍(metformin)[44]、黃連素[45]等;2) AMP類似物的前體化合物,如5-氨基-4-甲酰胺咪唑核糖核苷酸(5-aminoimidazole-4-carboxamide ribonucleoside,AICAR)[46]和近幾年被發(fā)現(xiàn)的一種膦酸類化合物5-(5-hydroxyl-isoxazol-3-yl)-furan-2-phosphonic acid[47],這些化合物可在細(xì)胞內(nèi)轉(zhuǎn)變?yōu)锳MP類似物,從而直接提高AMP水平使AMPK被激活;3)AMPK激活劑，可直接作用于AMPK使之構(gòu)象發(fā)生變化并隨后被激活,包括最早發(fā)現(xiàn)的被命名為A769662的化合物[48]以及最近發(fā)現(xiàn)的991[49]和MT-63-78[50]．在上述這些藥物中,二甲雙胍是一個(gè)重要的代表性藥物,已被廣泛應(yīng)用于治療Ⅱ型糖尿病,它能通過激活A(yù)MPK來緩解脂肪肝并降低并發(fā)癥風(fēng)險(xiǎn)[51]．

為了進(jìn)一步探究Ragulator-AXIN在藥理情況下對AMPK激活過程的調(diào)控作用,本課題組對缺失了LAMTOR1的小鼠胚胎成纖維細(xì)胞(mouse embryonic fibroblast,MEF)進(jìn)行二甲雙胍處理,發(fā)現(xiàn)二甲雙胍不能在這些細(xì)胞中激活A(yù)MPK；同樣地,對于LAMTOR1肝臟特異性敲除的小鼠,二甲雙胍也不能在其肝臟中激活A(yù)MPK；進(jìn)而在缺失了AXIN的細(xì)胞和小鼠肝臟中檢測了二甲雙胍對AMPK的激活作用,發(fā)現(xiàn)AXIN是二甲雙胍激活A(yù)MPK所必需的，且二甲雙胍激活A(yù)MPK也是通過溶酶體途徑進(jìn)行的,并依賴于上述溶酶體上的v-ATPase-Ragulator感應(yīng)復(fù)合體[52]．這一發(fā)現(xiàn)不僅解決了二甲雙胍如何激活A(yù)MPK的重要問題,還為人們了解二甲雙胍降低糖尿病人的腫瘤發(fā)生機(jī)制打開了窗口．

3　AMPK和葡萄糖感應(yīng)

引自參考文獻(xiàn)[59],經(jīng)修改．圖4　細(xì)胞感知葡萄糖水平的分子機(jī)制Fig.4 Molecular mechanism of glucose sensing in cell

葡萄糖是生物界最基本、最主要的供能物質(zhì),故其水平和機(jī)體的能量代謝狀態(tài)本身就具有緊密的聯(lián)系；此外,葡萄糖代謝的中間產(chǎn)物又是幾乎所有合成代謝途徑最重要的原材料來源．可見,感受葡萄糖的水平并隨時(shí)作出相應(yīng)的響應(yīng)是生物體維持代謝平衡的基本功能．AMPK能夠響應(yīng)機(jī)體葡萄糖水平的變化,并在其水平下降的時(shí)候被激活,該機(jī)制在各種表達(dá)有AMPK的真核生物中高度保守,從酵母到哺乳動物中都已被發(fā)現(xiàn)[53],是進(jìn)化上少有的經(jīng)典表型．

饑餓、運(yùn)動等生理過程都會導(dǎo)致整體或某個(gè)器官的葡萄糖水平變化．在葡萄糖水平下降時(shí),激活的AMPK能夠通過一系列方式維持代謝平衡和機(jī)體的正常生理功能．例如：饑餓能夠引起血液和組織液中葡萄糖水平的下降,AMPK在此時(shí)被激活,進(jìn)而促進(jìn)肝臟等組織中脂肪酸的β-氧化,使之轉(zhuǎn)換為利用脂肪酸[7];與此同時(shí),AMPK還能促進(jìn)肝臟生成酮體,通過血液供給腦部等不能利用脂肪酸的器官,以滿足這些組織的能量需求．許多生物的生命活動有晝夜節(jié)律(circadian rhythms),這種周期性也引起了機(jī)體內(nèi)葡萄糖水平的周期性變化[54]，而AMPK能夠響應(yīng)這種變化并維持機(jī)體能量穩(wěn)態(tài)[55]．近年來,人們利用AMPK和葡萄糖之間的密切聯(lián)系開發(fā)了許多藥物，來模擬葡萄糖缺失的情況以激活A(yù)MPK,如無法被代謝的葡萄糖類似物2-DG和5-TG等[56-57],這些藥物能夠通過阻斷葡萄糖代謝達(dá)到激活A(yù)MPK的目的,并已應(yīng)用于某些腫瘤的前期實(shí)驗(yàn)中[58]．

因此,葡萄糖水平的感應(yīng)對于AMPK的激活至關(guān)重要,是打開代謝穩(wěn)態(tài)維持機(jī)制之門的“鑰匙”．然而,AMPK如何感應(yīng)機(jī)體的葡萄糖水平并被激活的機(jī)制長期以來并不清楚,甚至存在重大的誤區(qū)．由于AMP在AMPK激活過程中的重要而經(jīng)典的地位,它一直以來被認(rèn)為是AMPK唯一的激活信號；同時(shí)，傳統(tǒng)的理論把葡萄糖看作一種“能量信號”,它的下降將引起細(xì)胞內(nèi)ATP水平的下降和AMP水平的上升,后者作為激活劑直接激活A(yù)MPK．但實(shí)際上,并沒有一種生理狀態(tài)能夠驗(yàn)證以上理論．

本課題組在對AMPK激活機(jī)制的深入研究中發(fā)現(xiàn),無論是在葡萄糖缺乏的細(xì)胞培養(yǎng)條件下,還是在饑餓的低血糖動物體內(nèi),都不能檢測到AMP水平的上升,但與此同時(shí)AMPK卻處在被激活的狀態(tài),這說明葡萄糖水平的降低與“能量缺失”無關(guān),即與AMP水平無關(guān),而是通過一種新的信號和一條獨(dú)立于能量代謝的通路來調(diào)控AMPK的激活．

本課題組之前已經(jīng)發(fā)現(xiàn)了一條響應(yīng)葡萄糖缺失并激活A(yù)MPK的溶酶體途徑[42],揭示了內(nèi)源AMPK的激活過程．在此基礎(chǔ)上,進(jìn)一步研究AMPK感受和響應(yīng)葡萄糖水平而被激活的機(jī)制,成功地鑒定出傳遞葡萄糖水平的“信使”——果糖1,6-二磷酸(fructose-1,6-bisphosphate,FBP),同時(shí)找到了感應(yīng)這一“信使”的“感受器”——參與糖酵解通路的醛縮酶(aldolase),依靠這一套完整的信號系統(tǒng),葡萄糖水平就能夠作為一種具體的信號調(diào)節(jié)AMPK的激活乃至整個(gè)機(jī)體的代謝穩(wěn)態(tài)[59]．具體地說,當(dāng)葡萄糖水平下降時(shí),葡萄糖代謝物FBP的水平也相應(yīng)地下降,該過程進(jìn)一步被醛縮酶所感應(yīng),后者將啟動激活A(yù)MPK的溶酶體途徑進(jìn)而介導(dǎo)AMPK的激活(圖4)．

這一發(fā)現(xiàn)改變了人們一直以來認(rèn)為的AMPK活性只被代表低能量的AMP調(diào)節(jié)的觀點(diǎn),是對傳統(tǒng)AMPK激活機(jī)制的一次重新認(rèn)識；并據(jù)此提出,葡萄糖水平是機(jī)體的一種“狀態(tài)信號”,通過調(diào)節(jié)AMPK的激活從而調(diào)節(jié)機(jī)體代謝的總平衡．這對全面了解細(xì)胞代謝穩(wěn)態(tài)維持的分子機(jī)制、糖代謝和相關(guān)應(yīng)激反應(yīng)乃至生理、病理進(jìn)程有重要意義,且有助于為研發(fā)治療人類重大疾病的藥物提供全新、有效的靶點(diǎn)．

4　AMPK和疾病

糖尿病是一種糖脂代謝穩(wěn)態(tài)失調(diào)、紊亂的疾?。延醒芯堪l(fā)現(xiàn),在肥胖小鼠和Ⅱ型糖尿病病人的外周組織中,AMPK的活性明顯被抑制[60-61]．而AMPK的激活能夠促進(jìn)肌肉中的葡萄糖轉(zhuǎn)運(yùn)蛋白GLUT4轉(zhuǎn)移到細(xì)胞膜上[62-63],增加肌肉對血液中葡萄糖的吸收和分解代謝,從而降低血糖[64]．在肝臟中,當(dāng)ATP缺乏引起AMPK的激活后，AMPK可以通過磷酸化轉(zhuǎn)錄輔激活因子CRTC2(也稱TORC2)促進(jìn)其出核,或者通過磷酸化去乙酰化酶HDAC4/5/7促進(jìn)轉(zhuǎn)錄因子FOXO1出核,這兩種方式的結(jié)果都是抑制肝臟的糖異生途徑,從而降低血糖[65-67]．

除了代謝性疾病,許多腫瘤的發(fā)生和代謝紊亂也有著密切的聯(lián)系．腫瘤以及腫瘤微環(huán)境與正常組織相比的一個(gè)重要特征就是代謝過程的不同,而代謝紊亂進(jìn)一步促進(jìn)了腫瘤的發(fā)生和發(fā)展[68-69]．由于腫瘤組織的快速增殖消耗大量營養(yǎng),腫瘤微環(huán)境是一個(gè)營養(yǎng)匱乏的環(huán)境,這將引起腫瘤組織中AMPK的激活[70]．在細(xì)胞水平上,已經(jīng)有大量的研究表明AMPK的激活可以通過抑制mTORC1復(fù)合體而抑制腫瘤細(xì)胞的合成代謝,從而阻止其增殖[71]；還可以通過促進(jìn)p53的活性引起腫瘤細(xì)胞的生長阻滯和凋亡,從而抑制腫瘤細(xì)胞的生長[72-74]．因此,在多種腫瘤組織,如黑色素瘤、乳腺癌、結(jié)腸癌和肺癌組織中,AMPK的表達(dá)或者活性被強(qiáng)烈抑制,進(jìn)一步打破了這些組織中原有的合成代謝和分解代謝的平衡,加劇了腫瘤的發(fā)展[70,75-76]．腫瘤微環(huán)境對免疫細(xì)胞中AMPK的激活則反過來阻止了促炎癥免疫細(xì)胞的分化和發(fā)育以及相關(guān)免疫因子的釋放,使之處于休眠狀態(tài)不能被激活并發(fā)揮效應(yīng),從而抑制了免疫反應(yīng)對腫瘤組織的識別和殺滅,導(dǎo)致腫瘤的生長更加不受控制[77]．

5　結(jié)語與展望

作為能量代謝調(diào)節(jié)的核心分子,AMPK一直是細(xì)胞代謝領(lǐng)域研究的重點(diǎn)．雖然近年來人們已經(jīng)在該領(lǐng)域獲得了一系列的新發(fā)現(xiàn),然而對AMPK精細(xì)的調(diào)控機(jī)制還需要更深層次的研究．目前已知AMPK的激活存在以下兩條截然不同的途徑:1) 依賴于AMP(AMP-dependent)的經(jīng)典途徑;2) 不依賴于AMP(AMP-independent)而通過糖酵解通路中代謝酶aldolase的途徑．那么,進(jìn)一步需要回答的重要問題就是細(xì)胞如何根據(jù)生理狀況對上述兩種途徑做出選擇．另外,本課題組的研究發(fā)現(xiàn)細(xì)胞中存在兩個(gè)激活A(yù)MPK的位置——溶酶體和細(xì)胞質(zhì)．那么,在這兩個(gè)位置上激活的AMPK是否有不同的底物及其生理意義也是后續(xù)研究中有待解決的問題，這不僅能夠幫助人們更深刻地理解AMPK以及代謝穩(wěn)態(tài)的調(diào)控機(jī)制,還有助于理解和操控相關(guān)的重要生理過程和病理過程,最終為戰(zhàn)勝威脅人類健康的重大疾病貢獻(xiàn)力量．

過去的十幾年來,人們也一直在研發(fā)以AMPK為靶點(diǎn)用于治療代謝性疾病的藥物,并已篩選出了一些潛在的AMPK激活劑,如國際制藥巨頭Pfizer公司篩選出的名為991的化合物．然而,這些激活劑雖然在體外實(shí)驗(yàn)中可以有效地激活A(yù)MPK,但其面臨的真正挑戰(zhàn)是能否在動物體內(nèi)以及人體內(nèi)也發(fā)揮同樣的功能．隨著人們對AMPK激活機(jī)制的不斷深入研究與解析,或許在不久的將來有望見證以全新的作用機(jī)制激活A(yù)MPK的藥物問世．

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