AMPK調(diào)控能量代謝研究進(jìn)展

陳 標(biāo)， 滿玉蓉， 高柳玲， 潘 慶

(華南農(nóng)業(yè)大學(xué) 海洋學(xué)院， 廣州 510642)

AMPK調(diào)控能量代謝研究進(jìn)展

陳 標(biāo)， 滿玉蓉， 高柳玲， 潘 慶

(華南農(nóng)業(yè)大學(xué) 海洋學(xué)院， 廣州 510642)

腺苷酸激活蛋白激酶(AMP-activated protein kinase, AMPK)作為重要的能量代謝激酶，廣泛存在于真核生物，在能量代謝調(diào)控中起重要作用。肝臟激酶B1(Liver kinase B1, LKB1)和鈣調(diào)素依賴蛋白激酶(Calmodulin-dependent protein kinases β，CaMKKβ)可激活A(yù)MPK。激活的AMPK通過對脂肪、蛋白質(zhì)和糖類代謝的調(diào)控維持體內(nèi)能量平衡。另外，AMPK調(diào)控因子激活劑與抑制劑、細(xì)胞因子可通過上調(diào)或下調(diào)AMPK表達(dá)，調(diào)控能量物質(zhì)代謝。

AMPK; 能量代謝; 激活劑與抑制劑; 細(xì)胞因子

AbstractAMP-activated protein kinase (AMPK) is widely existed in eukaryotes and has vital function in energy metabolism. AMPK could be activated by Liver kinase B1 (LKB1) and calmodulin-dependent protein kinases β (CaMKKβ)， and it regulates the metabolism of fat, protein and glucose to balance the energy metabolism. Moreover, activator, inhibitor and cytokines regulate energy metabolism through up-regulation or down-regulation of AMPK expression.

KeywordsAMPK； energy metabolism; activator and inhibitor; cytokines

AMPK是一種重要的細(xì)胞能量傳感器，能維持細(xì)胞能量平衡，在調(diào)節(jié)能量代謝中起重要作用[1]。它主要通過對能量物質(zhì)氧化、合成及轉(zhuǎn)錄關(guān)鍵酶活性調(diào)控，實現(xiàn)對能量物質(zhì)代謝調(diào)控[2-3]。目前，有關(guān)AMPK調(diào)控能量代謝機(jī)制尚未完全清楚[1]，在水產(chǎn)經(jīng)濟(jì)動物能量代謝調(diào)控方面研究更少，因此，有必要進(jìn)一步深入研究AMPK調(diào)控魚類能量代謝相關(guān)機(jī)制，為深入理解能量物質(zhì)吸收利用以及飼料配方優(yōu)化等方面提供理論基礎(chǔ)。本文對AMPK調(diào)控能量代謝相關(guān)機(jī)制及研究現(xiàn)狀進(jìn)行綜述。

1 AMPK分子結(jié)構(gòu)與組織分布

AMPK是由α、β、γ亞基組成的異源三聚體，α為催化亞基，β、γ為調(diào)節(jié)亞基[4]，每個亞基由不同基因型組成(α1、α2；β1、β2；γ1、γ2、γ3)，不同亞基之間12種組合構(gòu)成復(fù)雜的復(fù)合體[5]。其中，α亞基分為兩個功能區(qū)：N端為催化核心區(qū)，C端為β、γ亞基結(jié)合區(qū)；β亞基包含兩個保守區(qū)：糖原結(jié)合區(qū)與α、γ亞基結(jié)合區(qū)域；γ亞基包含4個串行重復(fù)CBS區(qū)域，該區(qū)域與AMPK和AMP連接有關(guān)[6]。AMPK各亞基組織分布不同，其中α亞基主要分布于肝臟、腎臟、腦、心臟、骨骼肌；β亞基主要分布于肝臟和骨骼?。沪脕喕诖蠖鄶?shù)組織中均有表達(dá)[7]。

2 AMPK激活調(diào)節(jié)

1978年證實AMPK上游激酶存在[8]，而直到近些年才發(fā)現(xiàn)LKB1和CaMKKβ可以磷酸化Thr-172，進(jìn)而激活細(xì)胞中AMPK活性[9-12]。LKB1主要分布于肝臟和肌肉等外周組織，CaMKKβ主要分布于中樞神經(jīng)系統(tǒng)[13]。研究表明，體外培養(yǎng)細(xì)胞和體內(nèi)骨骼肌細(xì)胞中AMPK都需要LKB1激活[10]，且LKB1活性表達(dá)需要AMP與AMPK結(jié)合[14]。CaMKKβ活性表達(dá)主要依賴于細(xì)胞內(nèi)鈣離子濃度變化，進(jìn)而調(diào)控Thr-172磷酸化[15]。LKB1和CaMKKβ調(diào)控AMPK活性途徑如圖1。

圖1 AMPK蛋白激酶信號通路代謝調(diào)控[16]

3 AMPK調(diào)控能量代謝

AMPK為細(xì)胞能量代謝中樞，主要通過調(diào)控脂肪、蛋白質(zhì)與糖合成與轉(zhuǎn)化，維持細(xì)胞內(nèi)能量代謝平衡[17-19]，在細(xì)胞能量代謝過程起重要作用，具體調(diào)控途徑如圖2。

圖2 AMPK蛋白激酶調(diào)控能量代謝[4]

3.1 AMPK調(diào)控脂肪代謝

AMPK對細(xì)胞脂肪代謝起著重要的作用，并且受營養(yǎng)物質(zhì)及細(xì)胞因子等因素的影響[20]。AMPK對脂肪代謝調(diào)控，主要通過調(diào)節(jié)脂代謝轉(zhuǎn)錄因子，實現(xiàn)脂肪氧化、合成及轉(zhuǎn)錄關(guān)鍵酶基因表達(dá)調(diào)控，其轉(zhuǎn)錄因子主要為過氧化物酶體增殖物激活受體(Phosphatidy inositol 3-kinase, PPAR)、固醇調(diào)節(jié)元件結(jié)合蛋白(Sterol regulatory element binding protein 1c, SREBP-1c)和碳水化合物反應(yīng)元件結(jié)合蛋白(Carbohydate responsive element-binding protein, ChREBP)[2-3]。侯祥紅通過添加不同濃度共軛亞麻酸(Conjugated linoleic acid, CLA)于體外培養(yǎng)人體肝癌細(xì)胞HepG2，結(jié)果顯示隨著CLA濃度升高，AMPKα磷酸化逐漸下降，同時乙酰輔酶A羧化酶(Acetyl-CoA carboxylase, ACC)表達(dá)水平升高，增加了HepG2細(xì)胞的脂質(zhì)沉積[21]。王瑾通過棕櫚酸鈉和大麻素Ⅰ型受體抑制劑ZH-101-S處理Hep-2細(xì)胞，發(fā)現(xiàn)磷酸化的AMPK，可以增強線粒體氧化作用，發(fā)揮減脂作用[22]。李心慰通過研究非酯化脂肪酸(Non-esterified fatty acids, NEFAs)調(diào)控奶牛肝細(xì)胞脂肪代謝AMPK代謝信號機(jī)制，表明NEFAs可以上調(diào)LKB1，促進(jìn)AMPKα磷酸化與PPARα表達(dá)及轉(zhuǎn)錄活性，上調(diào)脂氧化基因表達(dá)[13]。同時，激活的AMPKα抑制SREBP-1c和ChREBP的表達(dá)和轉(zhuǎn)錄活性，下調(diào)脂合成基因的表達(dá)。另外，Park等發(fā)現(xiàn)亞麻酸可以激活小鼠肝臟中AMPK活性，抑制SREBP-1c表達(dá)，減少脂肪沉淀[23]。

3.2 AMPK 調(diào)控蛋白質(zhì)代謝

激活的AMPK可以促進(jìn)蛋白質(zhì)分解，維持機(jī)體內(nèi)能量的平衡。激活的AMPK主要通過調(diào)控因子真核延長因子2激酶(EEF2K)調(diào)節(jié)真核延長因子-2(eEF-2)、結(jié)節(jié)性硬化復(fù)合體2(TSC2)、哺乳動物雷帕霉素靶目標(biāo)(mTOR)，調(diào)控蛋白質(zhì)合成與代謝[18]。馬延超發(fā)現(xiàn)AMPK活化后，可以降低大鼠絲氨酸/蘇氨酸蛋白激酶(AKT)磷酸化，活化Akt-FoxO信號通路，調(diào)控mafbx、murf1 表達(dá)，促進(jìn)骨骼肌蛋白質(zhì)降解[24]。Garcia-pereto研究顯示熱量限制作用可以激活A(yù)MPK-PI3K-AKT-eNOS通路[25]。Librán-Pérez等通過分析攝食不同脂肪水平飼料的虹鱒，首次證明虹鱒魚下丘腦存在AMPK，mTOR及AKT調(diào)控蛋白，并發(fā)現(xiàn)投喂高脂飼料的虹鱒魚饑餓3 h，AMPK磷酸化水平降低而mTOR磷酸化水平上升，AMPK與mTOR之間存在負(fù)調(diào)控關(guān)系[26]。此外，Zhou等也表明Ciclopirox olamine (CPX)可以通過激活A(yù)MPK，抑制mTORC1信號通路[27]。

3.3 AMPK調(diào)控糖代謝

AMPK對糖代謝調(diào)控主要通過促進(jìn)葡萄糖攝取及降低血糖作用，維持體內(nèi)能量物質(zhì)平衡。研究表明，激活的AMPK參與調(diào)控肝臟糖異生作用，抑制肝臟中G6Pase啟動子活性與葡萄糖產(chǎn)生[28]。另外，激活的AMPK可以抑制肝細(xì)胞中磷酸丙酮酸羧化酶(phosphoenolpyruvate carboxykinase, PEPCK)調(diào)控糖異生途徑[19]。鄒豐發(fā)現(xiàn)黃氏多糖(APS)在體外可活化小鼠骨骼肌細(xì)胞系C2C12的AMPK，并主要通過AMPK途徑增加其葡萄糖攝取，同時APS也能增加小鼠骨骼肌細(xì)胞系C2C12細(xì)胞高糖狀態(tài)下的AMPK活性，提高細(xì)胞的葡萄糖攝取[29]。Jin等發(fā)現(xiàn)黃酮苷提取物可以刺激AMPK和ACC通路磷酸化，并提高IR-HepG2細(xì)胞對葡萄糖的消耗[30]。張夏南研究表明荸薺提取物能夠顯著激活A(yù)MPK蛋白磷酸化、抑制小鼠肝臟pgc-1α和pepck表達(dá)，促進(jìn)葡萄糖代謝[31]。另外，Magnoni首次在魚類骨骼肌中發(fā)現(xiàn)，AMPK可以潛在刺激糖類吸收與利用[32]。

4 AMPK調(diào)控因子的作用

AMPK對能量代謝調(diào)控主要是通過調(diào)控能量物質(zhì)合成與氧化分解，維持細(xì)胞內(nèi)能量代謝平衡。目前，關(guān)于AMPK調(diào)控因子的研究主要集中于激活劑與抑制劑、細(xì)胞因子等對AMPK活性調(diào)控。

4.1 激活劑與抑制劑的作用

廖波通過研究激活劑5-氨基-4-咪哇梭基酞氨核普(5-aminoimidazole-4-carboxamide ribonucleoside, AICAR)和抑制劑8-溴-腺甘一磷酸(Br8-AMP)對豬肝細(xì)胞中AMPK活性影響，發(fā)現(xiàn)豬肝細(xì)胞在AICAR作用30和60 min后，AMPK活性分別升高8.11%和46.20%，而豬肝細(xì)胞在Br8-AMP作用30和60 min后AMPK活性分別降低9.13%和22.39%[33]。Jung等發(fā)現(xiàn)添加AICAR和二甲雙胍后能提高人肝癌細(xì)胞和小鼠原代肝細(xì)胞SREBP-1活性[34]。馮學(xué)敏研究了氟西汀對小鼠肝臟和肝臟原代細(xì)胞脂肪代謝影響，結(jié)果表明氟西汀可以引起AMPK表達(dá)下調(diào)[35]。宋科標(biāo)發(fā)現(xiàn)羅漢果苷元具有較好的激活A(yù)MPKa的藥理活性作用[36]。Deng等通過研究AMPK抑制劑對牛肝細(xì)胞脂代謝影響，發(fā)現(xiàn)添加AMPK抑制劑能降低ppara、chrebp表達(dá)，抑制脂肪合成[37]。

有關(guān)激活劑與抑制劑在魚類AMPK調(diào)控能量代謝的研究較少。Lau 等通過在培養(yǎng)基中添加激活劑AICAR，發(fā)現(xiàn)AICAR能夠顯著提高金魚肝細(xì)胞中AMPKα磷酸化及活性[38]。另外，培養(yǎng)基中添加AICAR能增加斑馬魚囊胚細(xì)胞中AMPKα磷酸化水平并降低mTOR轉(zhuǎn)錄表達(dá)水平[39]。

4.2 細(xì)胞因子應(yīng)用

有關(guān)細(xì)胞因子調(diào)控AMPK活性的研究，主要通過瘦素、脂聯(lián)素、胰島素、生長素等激素，在整體水平上對能量平衡進(jìn)行調(diào)節(jié)[11, 40]，但這些激素或細(xì)胞因子調(diào)節(jié)AMPK具體分子機(jī)制尚未清楚[1]。

瘦素主要在動物脂肪組織中產(chǎn)生[41]，瘦素含量和體脂肪與饑餓狀態(tài)有一定關(guān)系[42]。目前，關(guān)于瘦素對AMPK的調(diào)控已在不同種類硬骨魚中進(jìn)行研究，如大馬哈魚[43]、虹鱒魚[44]、條紋黑鱸[44]。Minokoshi研究表明，瘦素可以促進(jìn)AMPK磷酸化，抑制acc表達(dá)，刺激脂肪氧化[45]。宋玉峰等通過研究瘦素對黃顙魚肝臟脂肪代謝影響，表明瘦素可以降低肝臟組織脂肪含量并下調(diào)脂肪合成相關(guān)酶活性及轉(zhuǎn)錄因子表達(dá)[46]。Song等發(fā)現(xiàn)腹腔注射瘦素能夠顯著降低黃顙魚肝臟脂肪含量，同時，瘦素可以降低黃顙魚肝細(xì)胞中TG濃度，提高pparγ、cpt-1表達(dá)量，減少肝細(xì)胞脂肪沉積[47]。

脂聯(lián)素具有調(diào)節(jié)代謝作用，能促進(jìn)游離脂肪酸的氧化，降低血液中甘油三酯濃度，進(jìn)而調(diào)控能量平衡[48]。Yoon等研究發(fā)現(xiàn)脂聯(lián)素可以激活小鼠肌肉細(xì)胞中AMPK及PPAR活性，同時促進(jìn)aco、cpt1和fabp3表達(dá)量，提高肌肉細(xì)胞中脂肪氧化水平[49]。Gan等指出脂聯(lián)素可以通過激活A(yù)MPK/ACC2通路抑制雞脂肪細(xì)胞的脂肪合成[50]。Chen 等在細(xì)胞水平研究脂聯(lián)素對脂代謝影響，發(fā)現(xiàn)脂聯(lián)素能夠上調(diào)奶牛肝細(xì)胞AMPK磷酸化及SREBP-1c, ChREBP表達(dá)水平，促進(jìn)脂肪氧化與脂肪累積[51]。Awazawa等發(fā)現(xiàn)脂聯(lián)素可以通過AdipoR1/LKB1/AMPK通路抑制SREBP1c表達(dá)，調(diào)控肝細(xì)胞脂肪合成[52]。有關(guān)脂聯(lián)素在魚類能量代謝通路的研究較少，Sanchez-aurmaches等研究結(jié)果顯示，脂聯(lián)素可以激活虹鱒魚AKT通路，影響脂肪酸攝取與氧化，同時也發(fā)現(xiàn)在不同生理條件下脂聯(lián)素表現(xiàn)出不同調(diào)控作用[53]。

胰島素是體內(nèi)唯一的降低血糖激素，同時可以促進(jìn)糖、脂、蛋白質(zhì)合成。丁紅研通過研究胰島素對牛肝細(xì)胞脂代謝的影響，結(jié)果表明肝細(xì)胞經(jīng)過胰島素處理，AMPK磷酸化水平降低，SREBP-1c 和ChREBP轉(zhuǎn)錄活性及表達(dá)水平增加，同時上調(diào)脂肪合成相關(guān)基因表達(dá)，促進(jìn)脂肪合成[54]。Zheng等通過在黃顙魚腹腔分別注射濃度為0.1和1 μg/g胰島素，發(fā)現(xiàn)不同梯度組黃顙魚肝臟中PPARα1表達(dá)量差異顯著，在黃顙魚肝細(xì)胞培養(yǎng)基中添加濃度為100和1000 nmol/L胰島素，發(fā)現(xiàn)添加胰島素實驗組pparα1表達(dá)量顯著低于對照組[55]。

5 結(jié)語

AMPK廣泛存在于真核細(xì)胞中，在能量代謝調(diào)控中起重要作用。通過AMPK分子結(jié)構(gòu)、上下游靶基因、活性調(diào)節(jié)方面研究的開展，對AMPK功能及代謝調(diào)控機(jī)理已有初步認(rèn)知。然而，目前有關(guān)AMPK調(diào)控脂肪代謝研究尚存在一些亟須解決問題：1)有關(guān)AMPK調(diào)控脂肪能量代謝研究主要集中于相關(guān)轉(zhuǎn)錄因子活性及表達(dá)，今后應(yīng)結(jié)合分子生物學(xué)、生物化學(xué)等多種技術(shù)手段在細(xì)胞與整體水平上深入研究相關(guān)代謝調(diào)控機(jī)理。 2)AMPK調(diào)控脂肪代謝在水產(chǎn)經(jīng)濟(jì)動物中研究較少，應(yīng)加大水產(chǎn)經(jīng)濟(jì)動物AMPK調(diào)控脂肪代謝相關(guān)研究，推進(jìn)水產(chǎn)經(jīng)濟(jì)動物脂肪代謝調(diào)控機(jī)理認(rèn)知，將為水產(chǎn)經(jīng)濟(jì)動物飼料配方優(yōu)化及肉質(zhì)調(diào)控提供理論依據(jù)。

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The progress of AMPK in energy metabolism

CHEN Biao, MAN Yu-rong, GAO Liu-ling, PAN Qing

(College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China)

Q555

A

2095-1736(2017)05-0078-05

2016-09-22；

2016-10-13

廣東省科技廳研發(fā)與產(chǎn)業(yè)化項目(2013B090500028); 廣州市科技計劃項目(2014YZ-00208)

陳 標(biāo)，博士研究生，主要研究方向為水產(chǎn)經(jīng)濟(jì)動物營養(yǎng)與飼料，E-mail: chenbiao11@mails.ucas.ac.cn

潘 慶，教授，博士研究生導(dǎo)師，主要研究方向為水產(chǎn)經(jīng)濟(jì)動物營養(yǎng)與飼料，E-mail: qpan@scau.edu.cn

doi∶10.3969/j.issn.2095-1736.2017.05.078