王紹梅，李曉君，宋文明，潘聯(lián)云

普洱茶中沒食子酸及其改善飲食誘導(dǎo)的糖脂代謝紊亂研究進(jìn)展

王紹梅1,2，李曉君1,2，宋文明3，潘聯(lián)云4*

1. 滇西科技師范學(xué)院，云南省紅茶工程技術(shù)研究中心，云南 臨滄 677000；2. 滇西科技師范學(xué)院，生物技術(shù)與工程學(xué)院，云南 臨滄 677000；3. 臨滄高級(jí)技工學(xué)校，云南 臨滄 677000；4. 云南省農(nóng)業(yè)科學(xué)院茶葉研究所，云南省茶學(xué)重點(diǎn)實(shí)驗(yàn)室，云南 勐海 666200

糖脂代謝紊亂是引發(fā)心血管疾病、糖尿病和脂肪肝的重要原因之一。普洱茶中的沒食子酸能夠通過調(diào)節(jié)能量代謝和脂肪細(xì)胞分化、促進(jìn)葡萄糖吸收與利用、提高胰島素敏感性，進(jìn)而改善飲食誘導(dǎo)引起的葡萄糖和脂質(zhì)代謝紊亂。沒食子酸通過AMPK途徑、IR-Akt途徑以及PPAR-受體調(diào)節(jié)線粒體能量代謝、胰島素敏感性和葡萄糖吸收，從而維持糖脂代謝穩(wěn)態(tài)。本文綜述了普洱茶中的沒食子酸及其改善飲食誘導(dǎo)的糖脂代謝紊亂作用和作用機(jī)制的研究進(jìn)展。

普洱茶；沒食子酸；飲食誘導(dǎo)；糖脂代謝

葡萄糖和脂質(zhì)代謝紊亂與心血管疾病、糖尿病和脂肪肝等密切相關(guān)[1]。2014年，全世界有19億人超重，其中6億人存在肥胖問題，這主要是由于當(dāng)下全球飲食結(jié)構(gòu)變化引起的[2]。本文闡述了普洱茶中沒食子酸調(diào)節(jié)飲食誘導(dǎo)的糖脂代謝相關(guān)作用及其作用機(jī)制，為普洱茶調(diào)節(jié)糖脂代謝提供理論依據(jù)。

1 普洱茶沒食子酸概述

沒食子酸（Gallic acid，GA）又稱五倍子酸，化學(xué)名稱為3,4,5-三羥基苯甲酸，主要以酯的形式連接在兒茶素的3位羥基上，形成酯型兒茶素衍生物[3-4]。GA是普洱茶的特征性簡單酚類化合物，其含量在渥堆發(fā)酵過程中呈現(xiàn)先增加后下降的趨勢，總含量表現(xiàn)顯著增加[3-6]。

普洱茶中GA主要來源于曬青毛茶中的植物單寧化合物和兒茶素[7-9]（圖1）。在普洱茶渥堆發(fā)酵過程中，GA的含量與菌群種類和發(fā)酵條件密切相關(guān)[3]。曲霉菌等微生物分泌的單寧酶可使曬青毛茶中的小木麻黃素等多種沒食子單寧化合物分解形成GA[10-12]；表沒食子兒茶素沒食子酸酯（EGCG）和表兒茶素沒食子酸酯（ECG）等少部分酯型兒茶素在濕熱作用下水解生成GA[13-15]；簡單兒茶素（C）也能轉(zhuǎn)化形成GA，且GA含量變化與C呈現(xiàn)一定相關(guān)性，其相關(guān)系數(shù)分別為–0.869?3和–0.849?4[4]。在普洱茶渥堆發(fā)酵后期，GA在某些酶或微生物的次生代謝物作用下轉(zhuǎn)化成相應(yīng)的KMU-3等沒食子酸衍生物[16]，或與其他多酚發(fā)生氧化聚合[17]，均導(dǎo)致其含量降低。動(dòng)物生理試驗(yàn)表明，GA具有降糖降脂、抗菌、抗炎、抗腫瘤、抗突變等多種生物學(xué)作用[18-19]。

2 沒食子酸改善糖脂代謝作用的研究現(xiàn)狀

流行病學(xué)研究表明，普洱茶具有調(diào)節(jié)新陳代謝的作用[20-23]，長期飲用普洱茶能夠調(diào)節(jié)肥胖人群的內(nèi)臟脂肪含量、平均腰圍和身體質(zhì)量指數(shù)（Body mass index，BMI），有助于控制體重和預(yù)防代謝綜合征的發(fā)生[24]。普洱茶中GA可以通過降低血漿中甘油三酯、膽固醇和葡萄糖水平，調(diào)節(jié)脂肪細(xì)胞對葡萄糖的吸收，促進(jìn)線粒體能量代謝，提高胰島素敏感性和葡萄糖耐受性，改善飲食引起的糖脂代謝紊亂（圖2）。

2.1 沒食子酸調(diào)節(jié)血糖血脂水平

高糖高脂飲食會(huì)引起大鼠和小鼠代謝紊亂，引發(fā)高血糖和高血脂，降低胰島素敏感性和發(fā)生胰島素抵抗等現(xiàn)象[25-27]。GA能夠通過抑制腸道對脂質(zhì)的消化吸收、降低脂質(zhì)合成和積累、增加脂肪細(xì)胞分化和促進(jìn)葡萄糖吸收來調(diào)節(jié)糖脂代謝，改善葡萄糖和脂質(zhì)內(nèi)穩(wěn)態(tài)，降低葡萄糖毒性和脂毒性作用。

圖1 普洱茶后發(fā)酵過程中沒食子酸生成過程

注：↑表示升高，↓表示降低

2.1.1 抑制腸道對脂肪的消化和吸收

GA能夠通過抑制胰脂肪酶（Pancreatic lipase，LP）的活性來降低膳食脂肪的水解，減少腸道對甘油三酯的消化和吸收，從而降低餐后血液中甘油三酯水平。動(dòng)物試驗(yàn)研究發(fā)現(xiàn)，GA可以顯著抑制飲食玉米油乳劑后雄性ddY小鼠甘油三酯水平的升高[28]。體外試驗(yàn)表明，GA對LP活性的抑制呈劑量依賴性，且對LP的抑制活性為普洱茶提取物的11倍[29]。在GA抑制LP活性的過程中，普洱茶中兒茶素和多聚類黃酮等生物活性成分與GA具有協(xié)同作用，能夠提高GA的吸收率和穩(wěn)定性[28]。此外，GA能夠通過疏水作用或分子間氫鍵與膽酸鹽等血脂水平相關(guān)的生物分子結(jié)合，從而起到降血脂作用[30]。

2.1.2 降低脂質(zhì)合成和積累

在高脂飲食條件下，GA能夠抑制體重、肝臟器官重量、腹膜和附睪脂肪組織重量的增加[31-34]。Bak等[35]通過小鼠試驗(yàn)發(fā)現(xiàn)，GA能夠減小高脂飲食小鼠的附睪白色脂肪組織中脂肪細(xì)胞的大小。Hsu等[36]通過細(xì)胞試驗(yàn)發(fā)現(xiàn)，GA對3T3-L1前脂肪細(xì)胞群體增長也具有顯著抑制作用。Hsu[32]等研究表明，GA能夠降低高脂飲食誘導(dǎo)的雄性Wistar大鼠甘油三酯、磷脂、總膽固醇和低密度脂蛋白膽固醇水平，對其血脂異常具有顯著的抑制作用。同時(shí)，GA還能夠顯著降低飲食誘導(dǎo)的肥胖小鼠[35]和db/db小鼠[37]血糖濃度和血清甘油三酯水平。

Zeng等[29]研究發(fā)現(xiàn)，GA能夠劑量依賴性抑制3-羥基-3-甲基戊二酸單酰輔酶A還原酶（3-hydroxy-3-methyl glutaryl coenzyme A reductase，HMGR）的表達(dá)和提高卵磷脂膽固醇脂酰轉(zhuǎn)移酶（Lecithin-cholesterol acyltransferase，LCAT）的活性，從而抑制膽固醇合成和促進(jìn)膽固醇運(yùn)輸，降低血漿總膽固醇水平。此外，大量細(xì)胞試驗(yàn)表明，GA能夠降低3T3-L1脂肪細(xì)胞的膽固醇水平[37]，并能通過抑制HepG2細(xì)胞株脂肪酸和膽固醇合成相關(guān)酶的活性，降低其脂質(zhì)和膽固醇積累[38-39]。通過動(dòng)物試驗(yàn)發(fā)現(xiàn)，GA具有抑制高脂飲食誘導(dǎo)的大鼠磷脂和膽固醇酯合成的作用[32,40]。

2.1.3 促進(jìn)脂肪細(xì)胞對葡萄糖的吸收

脂肪組織在糖代謝中起著關(guān)鍵的作用[41-42]。在高糖飲食條件下，GA能夠促進(jìn)脂肪形成，增加脂肪組織對葡萄糖吸收，降低糖尿病大鼠空腹血糖水平，保護(hù)胰島細(xì)胞免受葡萄糖毒性損傷[31]。GA還能夠恢復(fù)高糖引起的葡萄糖和膽固醇水平異常，預(yù)防糖尿病發(fā)生[37]。體外試驗(yàn)表明，GA可以通過激活CCAA增強(qiáng)子結(jié)合蛋白（CCAAT/enhancer binding protein，C/EBP）和過氧化物酶體增殖物激活受體（Peroxisome proliferator-activated receptor-gamma，PPAR-）來刺激3T3-L1脂肪細(xì)胞分化，且GA呈濃度依賴性促進(jìn)3T3-L1脂肪細(xì)胞對葡萄糖的吸收，改善葡萄糖穩(wěn)態(tài)[37,43-45]。

2.1.4 調(diào)節(jié)糖異生和糖酵解作用

肝臟維持葡萄糖穩(wěn)態(tài)主要通過糖原生成和糖異生作用[46]。GA能夠增強(qiáng)肝臟糖酵解和糖原生成途徑，提高肝臟對葡萄糖的利用，改善高脂飲食誘導(dǎo)的糖尿病大鼠肝臟葡萄糖代謝異常。正常飲食條件下，胰島素通過信號(hào)轉(zhuǎn)導(dǎo)級(jí)聯(lián)促進(jìn)糖原合成酶（Glycogen synthase，GS）的表達(dá)，提高肝臟以糖原和脂質(zhì)形式儲(chǔ)存葡萄糖的能力，從而降低血糖水平[47-48]。高脂飲食會(huì)使大鼠血糖濃度升高，誘導(dǎo)糖尿病發(fā)生。GA可以通過下調(diào)糖尿病大鼠肝糖異生相關(guān)蛋白（如，果糖-1,6-二磷酸酶）和上調(diào)肝臟GS和糖酵解相關(guān)蛋白（如，己糖激酶、磷酸果糖激酶和醛糖酶）的表達(dá)調(diào)控葡萄糖代謝，促進(jìn)葡萄糖向糖原轉(zhuǎn)化，降低血糖水平[33]。

2.2 沒食子酸促進(jìn)線粒體能量代謝

GA能夠通過促進(jìn)線粒體能量代謝來提高葡萄糖耐量。通過研究嚙齒類動(dòng)物脂肪組織發(fā)現(xiàn)，上調(diào)線粒體膜內(nèi)解偶聯(lián)蛋白-1（Uncoupling protein 1，UCP1）能夠促進(jìn)能量消耗[49-51]。在不改變食物攝入量的情況下，GA通過提高UCP1表達(dá)來促進(jìn)線粒體能量代謝，提高產(chǎn)熱和新陳代謝，增加糖脂消耗率，從而降低體重并維持代謝平衡[34,52]。此外，GA還能夠激活腺苷酸活化蛋白激酶[Adenosine 5'-monophosphate (AMP)-activated protein kinase，AMPK]途徑，調(diào)控下游因子表達(dá)，通過直接刺激unc-15等自噬激酶或抑制雷帕霉素mTOR信號(hào)轉(zhuǎn)導(dǎo)來促進(jìn)自噬發(fā)生，從而清除受損線粒體，增強(qiáng)線粒體功能，提高能量代謝[53-57]。

2.3 沒食子酸改善胰島素抵抗和提高胰島素敏感性

高脂飲食誘導(dǎo)胰島素抵抗，從而導(dǎo)致葡萄糖攝取和利用率降低，血漿胰島素和血糖水平升高，最終引起糖尿病的發(fā)生[58-59]。提高胰島素敏感性和降低內(nèi)源性胰島素水平是治療糖尿病和代謝紊亂相關(guān)疾病的有效方法[60]。Variya等[37]研究表明，GA能夠提高3T3-L1脂肪細(xì)胞和db/db小鼠的胰島素敏感性；Hsu等[32]發(fā)現(xiàn)GA具有降低雄性Wistar大鼠血清胰島素和瘦素水平的作用。同時(shí)，GA還可以通過上調(diào)胰島素受體（Insulin receptor，IR），胰島素受體底物-1（Insulin receptor substrate-1，IRS-1），磷脂酰肌醇-3激酶（Phosphatidylinositol-3 kinase，PI3K）和Akt/蛋白激酶B（Akt/protein kinase B，Akt/PKB）等糖尿病大鼠肝臟胰島素信號(hào)轉(zhuǎn)導(dǎo)相關(guān)蛋白的表達(dá)，改善其胰島素抵抗，從而降低糖尿病大鼠空腹血糖和血漿胰島素水平[31,33]。

此外，脂肪組織對調(diào)節(jié)胰島素同樣具有重要作用。GA通過激活轉(zhuǎn)錄因子PPAR-和C/EBP刺激脂肪細(xì)胞分化，促進(jìn)脂聯(lián)素的表達(dá)和分泌，從而提高胰島素敏感性[61]。

3 沒食子酸調(diào)節(jié)糖脂代謝的機(jī)制研究現(xiàn)狀

在調(diào)節(jié)糖脂代謝過程中，GA通過激活A(yù)MPK來調(diào)控線粒體能量代謝和脂質(zhì)合成與積累，通過IR-Akt途徑調(diào)節(jié)胰島素敏感性與葡萄糖吸收，通過促進(jìn)PPAR-表達(dá)來改善胰島素抵抗、提高胰島素敏感性與葡萄糖耐受性（圖3）。

3.1 沒食子酸通過AMPK途徑調(diào)節(jié)線粒體能量代謝

AMPK作為細(xì)胞能量狀態(tài)傳感器，在細(xì)胞能量代謝、葡萄糖代謝和脂質(zhì)代謝中起著重要作用[62]。研究表明，GA能磷酸化小鼠肝臟、肌肉和肩胛間褐色脂肪組織中的AMPK，且效果高于二甲雙胍[34,52]?；罨腁MPK能直接激活下游因子PGC1-來增強(qiáng)線粒體功能[53,63-64]，也能夠通過激活下游靶基因Sirt1來去乙?；{(diào)控PCG1-[65-66]。

Sirt1是哺乳動(dòng)物能量穩(wěn)態(tài)的調(diào)節(jié)因子[67-68]。在白色脂肪組織和胰腺B細(xì)胞中，Sirt1缺失會(huì)影響胰島素分泌和葡萄糖攝取，同時(shí)降低能量消耗；提高Sirt1表達(dá)能夠增加胰島素分泌，增強(qiáng)葡萄糖耐量[69-70]。PGC1-是Sirt1下游基因，與線粒體氧化代謝相關(guān)。研究發(fā)現(xiàn)，GA通過上調(diào)線粒體基因PCG1-及其下游靶基因Tfam（線粒體轉(zhuǎn)錄因子）、Nrf-1（核呼吸因子-1）和Nrf-2來提高能量消耗，促進(jìn)代謝循環(huán)，而敲除Sirt1能夠抑制GA對PGC1的激活[52]。Sirt1可以激活磷酸烯醇丙酮酸羧化激酶（Phosphoenolpyruvate carboxykinase，PEPCK）和葡萄糖-6-磷酸酶（Glucose-6-phosphatase，G6Pase）等糖異生酶的基因表達(dá)來促進(jìn)葡萄糖生成[71]，但GA上調(diào)Sirt1不能促進(jìn)PEPCK和G6Pase的表達(dá)，這可能是由于活化的AMPK多向性作用導(dǎo)致的[52]。AMPK活化促進(jìn)小異二聚體伴侶（Small heterodimer partner，SHP）表達(dá)，而SHP對PEPCK和G6Pase表達(dá)有抑制作用[72]。

另有研究表明，GA能夠通過磷酸化HepG2細(xì)胞的AMPK來抑制乙酰輔酶A羧化酶（Acetyl-CoA carboxylase，ACC）及其下游脂質(zhì)合成因子的表達(dá)，從而減少脂質(zhì)的合成和積累[52-53,73]。此外，GA通過磷酸化AMPK促進(jìn)自噬清除受損線粒體，增強(qiáng)線粒體功能[56-57]。

注：→：激活、促進(jìn)或正調(diào)控；：抑制或負(fù)調(diào)控

3.2 沒食子酸通過IR-Akt途徑調(diào)節(jié)胰島素敏感性和葡萄糖吸收

Akt屬于絲氨酸/蘇氨酸蛋白激酶家族，受胰島素調(diào)節(jié)[74]。在正常條件下，胰島素與IR結(jié)合發(fā)生酪氨酸磷酸化[75]，磷酸化的IR能夠進(jìn)一步促進(jìn)下游信號(hào)分子IRS的表達(dá)和磷酸化，從而激活PI3K[47]，活化的PI3K通過激活A(yù)kt來調(diào)節(jié)胰島素敏感性和葡萄糖吸收[76]。Akt信號(hào)通路受阻會(huì)抑制4型葡萄糖轉(zhuǎn)運(yùn)蛋白（Glucose transporter type 4，Glut4）膜位移，減少葡萄糖轉(zhuǎn)運(yùn)和吸收，從而導(dǎo)致血糖升高和糖尿病發(fā)生[77-79]。

大量研究表明，GA能夠通過激活I(lǐng)R-Akt途徑增加胰島素敏感性以及葡萄糖的吸收和轉(zhuǎn)運(yùn)，維持血糖水平[37,80-81]。高脂飲食能夠誘導(dǎo)糖尿病大鼠肌肉組織中IR、IRS-1、PI3K和Akt的表達(dá)降低[82]，而GA可以改善并提高IR、IRS、PI3K和Akt表達(dá)，促進(jìn)Glut4和Glut2膜移位增強(qiáng)，維持正常的葡萄糖穩(wěn)態(tài)和胰島素敏感性[33]。此外，GA還能夠通過活化Akt來阻礙叉頭轉(zhuǎn)錄因子（Forkhead box O，F(xiàn)OXO）介導(dǎo)的PEPCK和G6Pase等糖異生酶的轉(zhuǎn)錄，從而抑制糖異生，減少葡萄糖生成[31,80]。

3.3 沒食子酸通過調(diào)節(jié)PPAR-γ維持糖代謝平衡

PPAR-屬于核受體超家族，在脂肪組織中高度表達(dá)，具有脂肪組織特異性[83]。PPAR-能夠促進(jìn)脂肪細(xì)胞分化，增加脂肪細(xì)胞數(shù)量，調(diào)節(jié)胰島素敏感性和糖脂質(zhì)代謝，維持脂質(zhì)和葡萄糖穩(wěn)態(tài)[84]。在高糖飲食條件下，GA能夠活化3T3-L1脂肪細(xì)胞的C/EBPs來上調(diào)PPAR-的表達(dá)[37]。PPAR-的上調(diào)表達(dá)可以促進(jìn)脂肪細(xì)胞分化，增加脂肪細(xì)胞對葡萄糖的吸收，降低葡萄糖毒性并提高葡萄糖耐受性[61]。病理學(xué)研究表明，GA能夠通過提高糖尿病大鼠和小鼠附睪脂肪組織的PPAR-表達(dá)來增加葡萄糖吸收，降低葡萄糖毒性[31, 36]。同時(shí)，PPAR-對PI3K也具有一定激活作用，PI3K活性的升高能夠促進(jìn)Glut4表達(dá)，從而提高葡萄糖轉(zhuǎn)運(yùn)和吸收，起到調(diào)節(jié)葡萄糖代謝的作用[85]。

4 總結(jié)與展望

GA是普洱茶特征性的生物活性成分，具有調(diào)控線粒體能量代謝，調(diào)節(jié)胰島素敏感性和葡萄糖吸收，維持脂質(zhì)和葡萄糖穩(wěn)態(tài)的作用。病理學(xué)研究和生物試驗(yàn)均表明，GA能夠通過抑制腸道對脂肪的消化和吸收、降低脂質(zhì)合成和積累、促進(jìn)脂肪細(xì)胞對葡萄糖的吸收、以及調(diào)節(jié)糖異生和糖酵解作用來調(diào)節(jié)血糖血脂水平。同時(shí)，GA還能夠促進(jìn)線粒體能量代謝、改善胰島素抵抗和提高胰島素敏感性，從而調(diào)節(jié)飲食誘導(dǎo)引起的糖脂代謝紊亂。本文綜述了普洱茶GA的代謝途徑及其生物學(xué)作用，為進(jìn)一步研究提高普洱茶中GA的積累和利用提供理論依據(jù)。

目前對GA的生物學(xué)作用研究已較為深入，但對其利用的研究還較少。因此提高普洱茶中GA的合成和積累，探討GA的利用方式以及進(jìn)一步深入研究GA在代謝過程中的作用是未來研究普洱茶功能成分的課題之一。

[1] Chen L, Chen X W, Huang X, et al. Regulation of glucose and lipid metabolism in health and disease [J]. Science China Life Sciences, 2019, 62: 1420-1458.

[2] Palermo A, Tuccinardi D, Defeudis G, et al. BMI and BMD: The potential interplay between obesity and bone fragility [J]. International Journal of Environmental Research and Public Health, 2016, 13(6): 544. doi: 10.3390/ijerph13060544.

[3] 折改梅, 張香蘭, 陳可可, 等. 茶氨酸和沒食子酸在普洱茶中的含量變化[J]. 云南植物研究, 2005, 27(5): 572-576. She G M, Zhang X L, Chen K K, et al. Content variation of theanine and gallic acid in Pu-er tea [J]. Acta Botanica Yunnanica, 2005, 27(5): 572-576.

[4] 吳楨. 普洱茶渥堆發(fā)酵過程中主要生化成分的變化[D]. 重慶: 西南大學(xué), 2008. Wu Z. The variation of chemical component during the fermentation procedure of Pu'er tea [D]. Chongqing: Southwest University, 2008.

[5] Pedan V, Rohn S, Holinger M, et al. Bioactive compound fingerprint analysis of aged raw Pu'er tea and young ripened Pu'er tea [J]. Molecules, 2018, 23(8): 1931. doi: 10.3390/molecules23081931.

[6] Shao W, Powell C, Clifford M N. The analysis by HPLC of green, black and Pu'er teas produced in Yunnan [J]. Journal of the Science of Food and Agriculture, 1995, 69(4): 535-540.

[7] Lv H P, Zhang Y J, Lin Z, et al. Processing and chemical constituents of Pu-erh tea: A review [J]. Food Research International, 2013, 53(2): 608-618.

[8] 周志宏, 楊崇仁. 云南普洱茶原料曬青毛茶的化學(xué)成分[J]. 云南植物研究, 2000(3): 343-350. Zhou Z H, Yang C R. Chemical constituents of crude green tea, the material of Pu-er tea in Yunnan [J]. Acta Botanica Yunnanica, 2000(3): 343-350.

[9] 張雯潔, 劉玉清, 李興從, 等. 云南“生態(tài)茶”的化學(xué)成分[J]. 云南植物研究, 1995(2): 204-208. Zhang W J, Liu Y Q, Li X C, et al. Chemical constituents of “Ecolocical tea” from Yunnan [J]. Acta Botanica Yunnanica. 1995(2): 204-208.

[10] Diepeningen A D V, Debets A J M, Varga J, et al. Efficient degradation of tannic acid by blackspecies [J]. Fungal Biology, 2004, 108(8): 919-925.

[11] Mukherjee G, Banerjee R. Biosynthesis of tannase and gallic acid from tannin rich substrates byand[J]. Journal of Basic Microbiology, 2004, 44(1): 42-48.

[12] 郭魯宏, 楊順楷. 利用固定化黑曲霉單寧酶制備沒食子酸的研究[J]. 生物工程學(xué)報(bào), 2000(5): 614-617. Guo L H, Yan S K. Study on gallic acid preparation by using immobilized tannase from[J]. Chinese Journal of Biotechnology, 2000(5): 614-617.

[13] Anaingsih V K, Sharma A, Zhou W. Green tea catechins during food processing and storage: A review on stability and detection [J]. Food Research International, 2013, 50(2): 469-479.

[14] Macedo J A, Ferreira L R, Camara L E, et al. Chemopreventive potential of the tannase-mediated biotransformation of green tea [J]. Food Chemistry, 2012, 133(2): 358-365.

[15] Tanaka T, Umeki H, Nagai S, et al. Transformation of tea catechins and flavonoid glycosides by treatment with Japanese post-fermented tea acetone powder [J]. Food Chemistry, 2012, 134(1): 276-281.

[16] Park Y, Lee J, Hong V S, et al. Identification of KMU-3, a novel derivative of gallic acid, as an inhibitor of adipogenesis [J]. Plos One, 2014, 9(10): e109344. doi: 10.1371/journal.pone.0109344.

[17] 呂海鵬, 林智, 谷記平, 等. 普洱茶中的沒食子酸研究[J]. 茶葉科學(xué), 2007, 27(2): 104-110. Lv H P, Lin Z, Gu J P, et al. Study on the gallic acid in Pu-erh tea [J]. Journal of Tea Science, 2007, 27(2): 104-110.

[18] 李肖玲, 崔嵐, 祝德秋. 沒食子酸生物學(xué)作用的研究進(jìn)展[J]. 中國藥師, 2004(10): 767-769. Li X L, Cui L, Zhu D Q. Research progress on the biological effects of gallic acid [J]. China Pharmacist, 2004(10): 767-769.

[19] 張冬英, 邵宛芳, 劉仲華, 等. 普洱茶中沒食子酸對過氧化物酶體增殖激活受體作用研究[J]. 營養(yǎng)學(xué)報(bào), 2009, 31(1): 47-50. Zhang D Y, Shao W F, Liu Z H, et al. Study of gallic acid in Pu-erh tea on the peroxisome proliferators activated receptors function [J]. Acta Nutrimenta Sinica, 2009, 31(1): 47-50.

[20] Gao X, Xie Q, Kong P, et al. Polyphenol- and caffeine-rich postfermented Pu-erh tea improves diet-induced metabolic syndrome by remodeling intestinal homeostasis in mice [J]. Infection and Immunity, 2017, 86(1): e00601-17. doi: 10.1128/IAI.00601-17.

[21] Huang H, Lin J. Pu-erh tea, green tea, and black tea suppresses hyperlipidemia, hyperleptinemia and fatty acid synthase through activating AMPK in rats fed a high-fructose diet [J]. Food & Function, 2012, 3(2): 170-177.

[22] Gong J, Peng C, Chen T, et al. Effects of theabrownin from Pu-erh Tea on the metabolism of serum lipids in rats: mechanism of action [J]. Journal of Food Science, 2010, 75(6): 182-189.

[23] Du W, Peng S, Liu Z, et al. Hypoglycemic effect of the water extract of Pu-erh tea [J]. Journal of Agricultural and Food Chemistry, 2012, 60(40): 10126-10132.

[24] Kubota K, Sumi S, Tojo H, et al. Improvements of mean body mass index and body weight in preobese and overweight Japanese adults with black Chinese tea (Pu-Erh) water extract [J]. Nutrition Research, 2011, 31(6): 421-428.

[25] Silva G, Ferraresi C, De Almeida R T, et al. Insulin resistance is improved in high-fat fed mice by photobiomodulation therapy at 630 nm [J]. Journal of Biophotonics, 2020, 13(3): e201960140. doi: 10.1002/jbio.201960140.

[26] Collison K S, Saleh S M, Bakheet R H, et al. Diabetes of the liver: the link between nonalcoholic fatty liver disease and HFCS-55 [J]. Obesity (Silver Spring, Md), 2009, 17(11): 2003-2013.

[27] Samuel V T. Fructose induced lipogenesis: from sugar to fat to insulin resistance [J]. Trends in endocrinology and metabolism: TEM, 2011, 22(2): 60-65.

[28] Oi Y, Hou I, Fujita H, et al. Antiobesity effects of Chinese black tea (Pu-erh tea) extract and gallic acid [J]. Phytotherapyresearch: PTR, 2012, 26(4): 475-481.

[29] Zeng L, Yan J, Luo L, et al. Effects of Pu-erh tea aqueous extract (PTAE) on blood lipid metabolism enzymes [J]. Food & Function, 2015, 6(6): 2008-2016.

[30] Zeng X, Sheng Z, Li X, et al.studies on the interactions of blood lipid level-related biological molecules with gallic acid and tannic acid [J]. Journal of the Science of Food and Agriculture, 2019, 99(15): 6882-6892.

[31] Gandhi G R, Jothi G, Antony P J, et al. Gallic acid attenuates high-fat diet fed-streptozotocin-induced insulin resistance via partial agonism of PPARγ in experimental type 2 diabetic rats and enhances glucose uptake through translocation and activation of GLUT4 in PI3K/p-Akt signaling pathway [J]. European Journal of Pharmacology, 2014, 745(15): 201-216.

[32] Hsu C, Yen G. Effect of gallic acid on high fat diet-induced dyslipidaemia, hepatosteatosis and oxidative stress in rats [J]. British Journal of Nutrition, 2007, 98(4): 727-735.

[33] Huang D W, Chang W C, Wu J S, et al. Gallic acid ameliorates hyperglycemia and improves hepatic carbohydrate metabolism in rats fed a high-fructose diet [J]. Nutrition Research, 2016, 36(2): 150-160.

[34] Paraíso A F, Sousa J N, Andrade J M, et al. Oral gallic acid improves metabolic profile by modulating SIRT1 expression in obese mice brown adipose tissue: A molecular and bioinformatic approach [J]. Life sciences, 2019, 237(11): 116914. doi: 10.1016/j.lfs.2019.116914.

[35] Bak E J, Kim J, Jang S, et al. Gallic acid improves glucose tolerance and triglyceride concentration in diet-induced obesity mice [J]. Scandinavian Journal of Clinical & Laboratory Investigation, 2013, 73(8): 607-614.

[36] Hsu C, Huang S, Yen G. Inhibitory effect of phenolic acids on the proliferation of 3T3-L1 Preadipocytes in Relation to their antioxidant activity [J]. Journal of Agricultural and Food Chemistry, 2006, 54(12): 4191-4197.

[37] Variya B C, Bakrania A K, Patel S S. Antidiabetic potential of gallic acid from: Improved glucose transporters and insulin sensitivity through PPAR-and Akt signaling [J]. Phytomedicine, 2019, 73: 152906. doi: 10.1016/j.phymed.2019.152906.

[38] 呂季樺, 孫璐西. 普洱茶抑制HepG2細(xì)胞株生合成膽固醇之有效成分探討[C]//中國茶葉學(xué)會(huì). 第四屆海峽兩岸茶業(yè)學(xué)術(shù)研討會(huì)論文集, 2006. Lv J H, Sun L X. Investigation of Pu-erh tea active principles to inhibitthe cholesterol synthesis in Hep G2cell line [C]// China Tea Scienc Society. The Fourth Cross-Straits Tea Industry Proceedings, 2006.

[39] Way T, Lin H, Kuo D, et al. Pu-erh tea attenuates hyperlipogenesis and induces hepatoma cells growth arrest through activating AMP-activated protein kinase (AMPK) in human HepG2 cells [J]. Journal of Agricultural and Food Chemistry, 2009, 57(12): 5257-5264.

[40] Elrokh E M, Yassin N A Z, Elshenawy S M, et al. Antihypercholesterolaemic effect of ginger rhizome () in rats [J]. Inflammopharmacology, 2010, 18(6): 309-315.

[41] Okuno A, Tamemoto H, Tobe K, et al. Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats [J]. Journal of Clinical Investigation, 1998, 101(6): 1354-1361.

[42] Chao L C, Marcussamuels B, Mason M, et al. Adipose tissue is required for the antidiabetic, but not for the hypolipidemic, effect of thiazolidinediones [J]. Journal of Clinical Investigation, 2000, 106(10): 1221-1228.

[43] Cao Z, Umek R M, Mcknight S L. Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells [J]. Genes & Development, 1991, 5(9): 1538-1552.

[44] Farmer S R. Transcriptional control of adipocyte formation [J]. Cell Metabolism, 2006, 4(4): 263-273.

[45] Furuyashiki T, Nagayasu H, Aoki Y, et al. Tea catechin suppresses adipocyte differentiation accompanied by down-regulation of PPARγ2 and C/EBPα in 3T3-L1 cells [J]. Bioscience, Biotechnology, and Biochemistry, 2004, 68(11): 2353-2359.

[46] Huang D W, Shen S C. Caffeic acid and cinnamic acid ameliorate glucose metabolism via modulating glycogenesis and gluconeogenesis in insulin-resistant mouse hepatocytes [J]. Journal of Functional Foods, 2012, 4(1): 358-366.

[47] Saltiel A R, Kahn C R. Insulin signalling and the regulation of glucose and lipid metabolism [J]. Nature, 2001, 414(6865): 799-806.

[48] Ferrer J C, Favre C, Gomis R R, et al. Control of glycogen deposition [J]. FEBS Letters, 2003, 546(1): 127-132.

[49] Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance [J]. Physiological Reviews, 2004, 84(1): 277-359.

[50] Oelkrug R, Polymeropoulos E T, Jastroch M. Brown adipose tissue: physiological function and evolutionary significance [J]. Journal of Comparative Physiology B-biochemical Systemic and Environmental Physiology, 2015, 185(6): 587-606.

[51] Bartelt A, Heeren J. Adipose tissue browning and metabolic health [J]. Nature Reviews Endocrinology, 2014, 10(1): 24-36.

[52] Doan K V, Ko C M, Kinyua A W, et al. Gallic acid regulates body weight and glucose homeostasis through AMPK activation [J]. Endocrinology, 2015, 156(1): 157-168.

[53] Oneill H M, Holloway G P, Steinberg G R. AMPK regulation of fatty acid metabolism and mitochondrial biogenesis: implications for obesity [J]. Molecular and Cellular Endocrinology, 2013, 366(2): 135-151.

[54] Hardie D G. AMPK: a target for drugs and natural products with effects on both diabetes and cancer [J]. Diabetes, 2013, 62(7): 2164-2172.

[55] Liesa M, Shirihai O S. Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure [J]. Cell Metabolism, 2013, 17(4): 491-506.

[56] Kim J, Kundu M, Viollet B, et al. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1 [J]. Nature Cell Biology, 2011, 13(2): 132-141.

[57] Zhao M, Klionsky D J. AMPK-dependent phosphorylation of ULK1 induces autophagy [J]. Cell Metabolism, 2011, 13(2): 119-120.

[58] Jermendy G. PPARγ agonists: Antidiabetic drugs with a potential role in the treatment of diseases other than diabetes [J]. Diabetes Research and Clinical Practice, 2007, 78(3): 29-39.

[59] Latha R C R, Daisy P. Insulin-secretagogue, antihyperlipidemic and other protective effects of gallic acid isolated fromRoxb. in streptozotocin-induced diabetic rats [J]. Chemico-Biological Interactions, 2011, 189(1): 112-118.

[60] Goldstein B J. Insulin resistance as the core defect in type 2 diabetes mellitus [J]. American Journal of Cardiology, 2002, 90(5): 3-10.

[61] Makihara H, Koike Y, Ohta M, et al. Gallic acid, the active ingredient of terminalia bellirica, enhances adipocyte differentiation and adiponectin secretion [J]. Biological & Pharmaceutical Bulletin, 2016, 39(7): 1137-1143.

[62] Hardie D G. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy [J]. Nature Reviews Molecular Cell Biology, 2007, 8(10): 774-785.

[63] Jager S, Handschin C, Stpierre J, et al. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1[J]. Proceedings of the National Academy of Sciences of the United States of America, 2007, 104(29): 12017-12022.

[64] Lagouge M, Argmann C A, Gerharthines Z, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1[J]. Cell, 2006, 127(6): 1109-1122.

[65] Canto C, Auwerx J. PGC-1α, SIRT1 and AMPK, an energy sensing network that controls energy expenditure [J]. Current Opinion in Lipidology, 2009, 20(2): 98-105.

[66] Fulco M, Cen Y, Zhao P, et al. Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of nampt [J]. Developmental Cell, 2008, 14(5): 661-673.

[67] Pfluger P T, Herranz D, Velascomiguel S, et al. Sirt1 protects against high-fat diet-induced metabolic damage [J]. Proceedings of the National Academy of Sciences of the United States of America, 2008, 105(28): 9793-9798.

[68] Michan S, Sinclair D C. Sirtuins in mammals: insights into their biological function [J]. Biochemical Journal, 2007, 404(1): 1-13.

[69] Kelly G. A Review of the sirtuin system, its clinical implications, and the potential role of dietary activators like resveratrol: part 1 [J]. Alternative Medicine Review: A Journal of Clinical Therapeutic, 2010, 15(3): 245-263.

[70] Ramadori G, Fujikawa T, Fukuda M, et al. SIRT1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity [J]. Cell Metabolism, 2010, 12(1): 78-87.

[71] Erion D M, Yonemitsu S, Nie Y, et al. SirT1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in diabetic rats [J]. Proceedings of the National Academy of Sciences of the United States of America, 2009, 106(27): 11288-11293.

[72] Kim Y D, Park K G, Lee Y S, et al. Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase-dependent regulation of the orphan nuclear receptor SHP [J]. Diabetes, 2008, 57(2): 306-314.

[73] Fullerton M D, Galic S, Marcinko K, et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin [J]. Nature Medicine, 2013, 19(12): 1649-1654.

[74] Kido Y, Nakae J, Accili D. The insulin receptor and its cellular targets [J]. The Journal of Clinical Endocrinology and Metabolism, 2001, 86(3): 972-979.

[75] White M F. Insulin signaling in health and disease [J]. Science, 2003, 302(5651): 1710-1711.

[76] Lietzke S E, Bose S, Cronin T C, et al. Structural basis of 3-phosphoinositide recognition by pleckstrin homology domains [J]. Molecular Cell, 2000, 6(2): 385-394.

[77] Kim Y B, Peroni O D, Franke T F, et al. Divergent regulation of Akt1 and Akt2 isoforms in insulin target tissues of obese Zucker rats [J]. Diabetes, 2000, 49(5): 847-856.

[78] Cho H, Mu J, Kim J K, et al. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKBβ) [J]. Science, 2001, 292(5522): 1728-1731.

[79] Katome T, Obata T, Matsushima R, et al. Use of RNA Interference-mediated gene silencing and adenoviral overexpression to elucidate the roles of AKT/Protein kinase B isoforms in insulin actions [J]. Journal of Biological Chemistry, 2003, 278(30): 28312-28323.

[80] Tzatsos A, Kandror K V. Nutrients suppress phosphatidylinositol 3-Kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation [J]. Molecular and Cellular Biology, 2006, 26(1): 63-76.

[81] Ma X, Tsuda S, Yang X, et al. Pu-erh tea hot-water extract activates Akt and induces insulin-independent glucose transport in rat skeletal muscle [J]. Journal of Medicinal Food, 2013, 16(3): 259-262.

[82] Tzeng T, Liou S, Liu I. Myricetin ameliorates defective post-receptor insulin signaling via-endorphin signaling in the skeletal muscles of fructose-fed rats [J]. Evidence-based Complementary and Alternative Medicine, 2011: 150752. doi: 10.1093/ecam/neq017.

[83] Soccio R E, Chen E R, Lazar M A. Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes [J]. Cell Metabolism, 2014, 20(4): 573-591.

[84] Plutzky J. PPARs as Therapeutic targets: reverse cardiology? [J]. Science, 2003, 302(5644): 406-407.

[85] Sharma B R, Kim H J, Rhyu D Y.extract ameliorates insulin resistance and regulates glucose metabolism in C57BL/KsJ-db/db mice via PI3K/AKT signaling pathway in myocytes [J]. Journal of Translational Medicine, 2015, 13(1): 62. doi: 10.1186/s12967-015-0412-5.

Research Progress of Gallic Acid in Puer Tea and Its Improvement of Diet Induced Glucose and Lipid Metabolism Disorder

WANG Shaomei1,2, LI Xiaojun1,2, SONG Wenming3, PAN Lianyun4*

1. Black Tea Engineering Research Center of Yunnan, West Yunnan university, Lincang 677000, China; 2. School of Biotechnology and Engineering, West Yunnan University, Lincang 677000, China; 3. Senior Technical School of Lincang, Lincang 677000, China; 4. Tea Research Institute, Yunnan Academy of Agricultural Sciences, Yunnan Provincial Key Laboratory of Tea Science, Menghai 666200, China

The disorder of glucose and lipid metabolism is one of the important causes of cardiovascular diseases, diabetes and fatty liver. Gallic acid of Puer tea can ameliorate diet induced glucose and lipid metabolism disorder through regulating energy metabolism and adipocyte differentiation, promoting glucose absorption and utilization, and increasing insulin sensitivity. Gallic acid regulates mitochondrial energy metabolism, insulin sensitivity and glucose absorption to maintain glucose and lipid metabolism homeostasis through AMPK and IR-Akt pathway and PPAR gamma receptor. In this review, we summarized gallic acid in Puer tea and its mechanism to improve the disorder of glucose and lipid metabolism induced by diet.

Puer tea, gallic acid, diet induced, glucose and lipid metabolism

S571.1

A

1000-369X(2020)04-431-10

2019-11-19

2019-12-05

王紹梅，女，教授，主要從事茶葉加工、審評(píng)和茶文化方面的研究，lc-wangshaomei@163.com。

Panly11@lzu.edu.cn

投稿平臺(tái)：http://cykk.cbpt.cnki.net