國(guó)立東，王麗群2，蔣琛，劉曉艷，劉莉莉

（1.黑龍江中醫(yī)藥大學(xué)藥學(xué)院，哈爾濱150040；2.黑龍江省農(nóng)業(yè)科學(xué)院食品加工研究所，哈爾濱150086）

乳酸菌調(diào)控體內(nèi)膽固醇代謝綜述

國(guó)立東1，王麗群2，蔣琛1，劉曉艷1，劉莉莉1

（1.黑龍江中醫(yī)藥大學(xué)藥學(xué)院，哈爾濱150040；2.黑龍江省農(nóng)業(yè)科學(xué)院食品加工研究所，哈爾濱150086）

心血管疾病已成為全球死亡率和發(fā)病率的首因，血清膽固醇水平過(guò)高是其主要危險(xiǎn)因素。目前，降低人體內(nèi)膽固醇水平的方法主要包括膳食干預(yù)和藥物治療，但藥物通常具有副作用。乳酸菌作為益生菌的主要來(lái)源，已通過(guò)動(dòng)物或人體臨床試驗(yàn)證實(shí)了其降膽固醇作用，至少能對(duì)血清總膽固醇、總甘油三酯、低密度脂蛋白膽固醇、高密度脂蛋白膽固醇中的一項(xiàng)及以上指標(biāo)有改善作用。乳酸菌可以通過(guò)調(diào)控體內(nèi)膽固醇的吸收轉(zhuǎn)運(yùn)、分解代謝和/或合成代謝相關(guān)基因表達(dá)的機(jī)制來(lái)降低機(jī)體內(nèi)膽固醇水平。不論是乳酸菌的體內(nèi)降膽固醇能力還是作用機(jī)制，都存在著菌株特異性。文中對(duì)上述內(nèi)容進(jìn)行了綜述，并對(duì)存在的問(wèn)題進(jìn)行了分析與展望，旨在為降膽固醇乳酸菌的深入研究提供參考。

乳酸菌；膽固醇；代謝；調(diào)控；機(jī)制

0 引 言

心血管疾病已成為中國(guó)乃至全球人群的主要死因之一[1,2]，血清膽固醇過(guò)高是引發(fā)冠心病的主要危險(xiǎn)因素[3]，人體血清總膽固醇每降低1%，冠心病發(fā)生的危險(xiǎn)性可降低2%～3%[4]。臨床應(yīng)用的他汀類降膽固醇藥物成本高且副作用明顯[5]，故天然的非藥物方法相繼提出，如乳酸菌的使用。乳酸菌已被人類大規(guī)模安全消費(fèi)數(shù)以千年[6,7]，為人體腸道正常有益菌群，在糖/脂代謝、肥胖、炎癥等方面發(fā)揮重要作用[8-10]。自Mann和Spoerry發(fā)現(xiàn)血清膽固醇與乳酸菌的相關(guān)性[11]，大量體內(nèi)外研究均證明了乳酸菌的降膽固醇能力，然而體內(nèi)試驗(yàn)特別是臨床數(shù)據(jù)則更為關(guān)鍵。因此，文中對(duì)降膽固醇乳酸菌的動(dòng)物及臨床試驗(yàn)證據(jù)，及其調(diào)控體內(nèi)膽固醇代謝機(jī)理進(jìn)行了總結(jié)，并對(duì)其存在的問(wèn)題進(jìn)行了分析與展望。

1 乳酸菌體內(nèi)降膽固醇作用

動(dòng)物與人體模型用于評(píng)價(jià)乳酸菌對(duì)機(jī)體血清膽固醇水平的影響已進(jìn)行了數(shù)十年，已有充分證據(jù)證明乳酸菌的降膽固醇能力，并且在降膽固醇的菌種成員中仍有一些新的乳酸菌菌種不斷出現(xiàn)。

1.1 動(dòng)物模型數(shù)據(jù)

動(dòng)物模型數(shù)據(jù)通常能間接反映人體內(nèi)的實(shí)際發(fā)生情況。因此，臨床前適宜的動(dòng)物模型通常被構(gòu)建進(jìn)而評(píng)價(jià)乳酸菌的潛在降膽固醇作用，如大鼠、小鼠、倉(cāng)鼠、豬、兔等動(dòng)物模型[12-23]的應(yīng)用。如果單純研究乳酸菌的降膽固醇作用，通常是構(gòu)建高膽固醇血癥模型動(dòng)物[12-13,16,19-23]，也有乳酸菌能降低酒精性肝病、II型糖尿病以及肥胖等模型動(dòng)物[14,17,18,24]體內(nèi)膽固醇水平的報(bào)道。目前，已報(bào)道可有效降低模型動(dòng)物體內(nèi)膽固醇水平的乳酸菌菌種有十余種，主要分布于乳桿菌屬、雙歧桿菌屬和腸球菌屬，其中以乳桿菌屬和雙歧桿菌屬菌株報(bào)道最多，具體見表1。在有降膽固醇活性的乳桿菌屬中，以嗜酸乳桿菌、植物乳桿菌、羅伊氏乳桿菌、鼠李糖乳桿菌、干酪乳桿菌等為常見，而雙歧桿菌屬中以長(zhǎng)雙歧桿菌、動(dòng)物雙歧桿菌乳亞種等為常見，腸球菌屬中主要為屎腸球菌。這些降膽固醇乳酸菌菌株主要來(lái)源于兩方面：一是來(lái)源于健康人體腸道或唾液，包括嬰幼兒、成人；二是來(lái)源于傳統(tǒng)發(fā)酵食品，如酸奶、干酪、馬奶酒等乳制品，泡菜、酸菜等植物性食品，發(fā)酵魚、香腸等肉制品。受試動(dòng)物攝入乳酸菌的方式多樣，包括直接制成懸液（懸于生理鹽水或脫脂乳中）定量灌胃動(dòng)物，以發(fā)酵食品（發(fā)酵乳、發(fā)酵谷物醬、酸面團(tuán)等）的形式定量給予動(dòng)物，甚至將菌種直接加到水或飼料中由動(dòng)物自由采食。乳酸菌給予受試動(dòng)物的劑量也不盡相同，從每天最低的104g-1有效劑量到最高達(dá)1013g-1飼料的高有效劑量，有效的干預(yù)周期從最短14 d到最長(zhǎng)70 d不等。檢測(cè)指標(biāo)通常以血清中總膽固醇（TC）、總甘油三酯（TG）、低密度脂蛋白膽固醇（LDL-C）、高密度脂蛋白膽固醇（HDL-C）為主，這些供試乳酸菌中至少能對(duì)其中一項(xiàng)指標(biāo)有改善作用。

綜上所述，乳酸菌降低模型動(dòng)物體內(nèi)膽固醇水平是顯而易見的。但是，上述報(bào)道中因選取的供試乳酸菌菌株不同，干預(yù)周期不同，劑量和給藥方式不同，故無(wú)法比較各菌株間降膽固醇能力的差異。此外，關(guān)于乳酸菌體內(nèi)降膽固醇作用的劑量-效應(yīng)關(guān)系方面的數(shù)據(jù)比較缺乏，如高、中、低三個(gè)劑量的實(shí)驗(yàn)設(shè)計(jì)。

1.2 臨床數(shù)據(jù)

乳酸菌降膽固醇作用的研究終究是為人類服務(wù)，而動(dòng)物模型數(shù)據(jù)并不能完全代表人體內(nèi)的真實(shí)情況，往往與人體試驗(yàn)數(shù)據(jù)存在一定偏差。因此，研究乳酸菌降膽固醇的作用，其人體臨床證據(jù)是非常必要與重要的。關(guān)于降膽固醇作用乳酸菌的臨床數(shù)據(jù)，如表2所示。目前，已經(jīng)過(guò)人體臨床試驗(yàn)的降膽固醇乳酸菌菌株也同樣集中在乳桿菌屬[25-31]和雙歧桿菌屬[29-32]兩個(gè)菌屬，也有嗜熱鏈球菌[31,33]和屎腸球菌[33,34]的應(yīng)用。這些菌株通常是單一菌種或混合菌種，以發(fā)酵酸乳或口服膠囊的形式給予受試人群，每天服用劑量一般在109～1012，服用周期一般在4～56周。受試群體為兒童、成人或老年人，多為高膽固醇血癥人群，也有II型糖尿病、非酒精性脂肪肝及健康人群為受試對(duì)象，均證明了受試乳酸菌人體內(nèi)的降膽固醇作用。然而，臨床試驗(yàn)中也有發(fā)現(xiàn)乳酸菌無(wú)降膽固醇作用的報(bào)道[35]，分析原因可能是人體臨床試驗(yàn)數(shù)據(jù)受外界因素影響較大，如受試人群飲食難于控制、個(gè)體差異大以及樣本數(shù)量少等。

表1 不同種屬代表性乳酸菌對(duì)模型動(dòng)物的降膽固醇作用

表2 乳酸菌降膽固醇作用的臨床證據(jù)

2 乳酸菌調(diào)控體內(nèi)膽固醇代謝的機(jī)制

機(jī)體內(nèi)膽固醇平衡主要受三個(gè)方面的調(diào)控，即膽固醇的合成、分解與吸收轉(zhuǎn)運(yùn)。若篩選降膽固醇活性藥物或食品，以此為切入點(diǎn)則更為直接。乳酸菌對(duì)膽固醇代謝調(diào)控機(jī)制主要是基于細(xì)胞及動(dòng)物模型提出，益生乳酸菌對(duì)膽固醇代謝調(diào)控的可能途徑如圖1所示。

圖1 乳酸菌調(diào)控膽固醇代謝的可能途徑

2.1 調(diào)控膽固醇吸收與轉(zhuǎn)運(yùn)

這種調(diào)控作用主要發(fā)生在小腸，可通過(guò)抑制膽固醇吸收、促進(jìn)膽固醇外排來(lái)降低體內(nèi)膽固醇水平。小腸對(duì)膽固醇吸收轉(zhuǎn)運(yùn)的調(diào)控主要由肝臟X受體（LXR s）介導(dǎo)，包括LXR-α和LXR-β（也稱作NR 1H 3和NR 1H 2），其屬于核受體，通過(guò)控制轉(zhuǎn)錄參與脂質(zhì)代謝。一旦被激活，LXR s能夠誘導(dǎo)膽固醇吸收、流出、轉(zhuǎn)運(yùn)和分泌相關(guān)的一系列基因的表達(dá)。比如，腸道膽固醇吸收的關(guān)鍵轉(zhuǎn)運(yùn)蛋白Niemann-Pick C1 Like 1（NPC1L1）[36]，激活LXRs可下調(diào)NPC1L1表達(dá)進(jìn)而抑制腸道對(duì)膽固醇的吸收。此外，LXR s的激活可介導(dǎo)腺苷三磷酸結(jié)合盒轉(zhuǎn)運(yùn)蛋白（ATP-binding cassette transpo rt）A 1（ABCA1）、G 1（ABCG 1）、G 5和G 8（ABCG 5/G 8）表達(dá)上調(diào)[37,38]，ABCA 1、ABCG 1、ABCG 5/G 8的過(guò)表達(dá)將增加膽固醇從腸細(xì)胞內(nèi)排出進(jìn)入腸腔，促進(jìn)體內(nèi)膽固醇的清除。乳酸菌可通過(guò)激活LXR s，從而介導(dǎo)NPC 1L1表達(dá)下調(diào)[39-41]、ABCG 5/ G8[41,42]、ABCA1和ABCG1[43]表達(dá)上調(diào)，進(jìn)而抑制膽固醇在體內(nèi)的吸收。除此之外，肝臟也可以調(diào)控膽固醇的吸收轉(zhuǎn)運(yùn)。肝臟低密度脂蛋白受體（LDLR）能調(diào)節(jié)機(jī)體血漿低密度脂蛋白膽固醇（LDL-C）的體內(nèi)平衡。肝臟LDLR表達(dá)增加，會(huì)通過(guò)受體介導(dǎo)的胞吞作用來(lái)提高血漿LDL-C的清除，LDLR表達(dá)主要受固醇調(diào)節(jié)元件結(jié)合蛋白（SREBPs，包括SREBP-1c和SREBP-2）的控制[44]。乳酸菌也可通過(guò)上調(diào)肝臟SREBP-2[24]和LDLR[24,45,46]表達(dá)的機(jī)理來(lái)降低動(dòng)物血清膽固醇水平。

2.2 促進(jìn)膽固醇分解代謝

降膽固醇的另一種方式就是促進(jìn)體內(nèi)膽固醇分解。膽固醇7α-羥化酶（CYP7A 1）是肝臟膽固醇分解代謝的限速酶，提高CYP7A 1活性便可降低體內(nèi)膽固醇濃度。膽酸（鹽）是膽固醇分解代謝的產(chǎn)物，在人體內(nèi)主要以牛磺膽酸鹽和甘氨膽酸鹽兩種結(jié)合態(tài)形式存在，并參與肝腸循環(huán)[47]。益生乳酸菌產(chǎn)生的BSH能將進(jìn)入腸道內(nèi)的結(jié)合型膽酸鹽水解成游離膽汁酸。一方面，生成的游離膽汁酸相比于結(jié)合型膽酸不容易被小腸吸收，大部分不參與肝腸循環(huán)而隨糞便直接排出體外，由于反饋調(diào)節(jié)作用導(dǎo)致膽固醇在肝臟內(nèi)被進(jìn)一步分解生成新的膽汁酸，從而降低體內(nèi)膽固醇水平[48]。另一方面，乳酸菌可通過(guò)提高肝臟CYP7A 1活性從而加速肝臟膽固醇分解來(lái)降低體內(nèi)膽固醇濃度[46,49,50]，而乳酸菌對(duì)CYP7A 1的調(diào)控作用，主要是通過(guò)其BSH活性而生成的游離膽汁酸作用于法尼醇X受體（FXR），抑制FXR活性，并由FXR介導(dǎo)下調(diào)小異源二聚體伴侶受體（SHP）的表達(dá)來(lái)完成[50]。由此可見，乳酸菌自身產(chǎn)生的BSH活性對(duì)其體內(nèi)降膽固醇作用的貢獻(xiàn)是雙重的。因此，是否具有BSH活性便成為體外篩選降膽固醇益生菌的首要條件。

2.3 抑制膽固醇體內(nèi)自身合成

抑制肝臟中膽固醇合成的限速酶—3-羥基-3-甲基戊二酸單酰輔酶A（HMG-CoA）還原酶活性即可降低體內(nèi)膽固醇水平。臨床上應(yīng)用已久的他汀類藥物就是通過(guò)這種機(jī)理來(lái)達(dá)到降膽固醇功效的。有研究報(bào)道，乳酸菌可通過(guò)調(diào)控HMG-CoA還原酶活性進(jìn)而降低大鼠血清膽固醇水平[45,51]，這種調(diào)控作用的可能機(jī)制是乳酸菌通過(guò)抑制SREBPs表達(dá)的途徑來(lái)降低HMG-CoA還原酶活性的[51]。

3 結(jié)論與展望

乳酸菌與體內(nèi)膽固醇代謝的關(guān)系已進(jìn)行了半個(gè)世紀(jì)的研究與探討，目前已有充分的證據(jù)證明乳酸菌可有效降低動(dòng)物或人體內(nèi)膽固醇水平，這是毋庸置疑的，盡管存在著菌株特異性。從整體上看，乳酸菌對(duì)模型動(dòng)物體內(nèi)膽固醇水平的降低程度普遍高于人體模型，這可能與模型動(dòng)物個(gè)體之間差異小和飲食易控制等因素有關(guān)。迄今為止，已有大量的降膽固醇乳酸菌保健食品或發(fā)酵產(chǎn)品在全球上市，如VSL#3[31]、Gaio[33]，以及上海光明乳業(yè)股份有限公司生產(chǎn)的“光明暢優(yōu)植物乳酸菌飲品”，其中具有獨(dú)立自主知識(shí)產(chǎn)權(quán)的植物乳桿菌ST-III是從傳統(tǒng)食品泡菜中篩選獲得的降膽固醇功能乳酸菌[52]。

相比于體外，乳酸菌體內(nèi)降膽固醇機(jī)制的研究相對(duì)滯后。近五年，隨著研究的深入，乳酸菌調(diào)控體內(nèi)膽固醇代謝的機(jī)制逐漸被揭示，研究人員主要從三個(gè)方面對(duì)此進(jìn)行了探究，即對(duì)體內(nèi)膽固醇的吸收轉(zhuǎn)運(yùn)、分解代謝以及合成代謝的影響。乳酸菌對(duì)體內(nèi)膽固醇代謝的調(diào)控機(jī)制，也同樣存在著菌株特異性。目前，乳酸菌對(duì)體內(nèi)膽固醇代謝調(diào)控機(jī)制的研究尚停留在現(xiàn)象階段，即經(jīng)過(guò)乳酸菌干預(yù)后，體內(nèi)膽固醇代謝相關(guān)基因出現(xiàn)了差異表達(dá)，便認(rèn)為乳酸菌是通過(guò)調(diào)控這些差異表達(dá)的基因來(lái)降低體內(nèi)膽固醇水平，缺乏本質(zhì)的發(fā)現(xiàn)。此外，乳酸菌對(duì)體內(nèi)膽固醇代謝調(diào)控的活性物質(zhì)是代謝產(chǎn)物還是細(xì)胞壁組分，是直接調(diào)控還是間接調(diào)控，間接調(diào)控又是怎樣的作用機(jī)理，這些都有待于深入挖掘。同時(shí)，隨著組學(xué)技術(shù)的發(fā)展，乳酸菌與體內(nèi)膽固醇代謝的關(guān)系將會(huì)得到更好的澄清。

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Regulation of cholesterol metabolism in vivo by Lactic acid bacteria:A review

GUO Li-dong1,WANG Li-qun2,JIANG Chen1,LIU Xiao-yan1,LIU Li-li1
(1.College of Pharmacy,Heilongjiang University o f Chinese Medicine,Harbin 150040,China;2.Food Processing Institute,Heilongjiang Academy of Agricultural Sciences,Harbin 150086,China)

Cardiovascular diseases(CVD)are the leading cause of global mortality and morbidity.Elevated serum cholesterol level is a contributory risk factor for the development of CVD.In human,current cholesterol-lowering methods include dietary intervention and drug therapy.However,all the drugs have severe side effects.As a main source of probiotic bacteria,lactic acid bacteria have shown a positive effect on the serum cholesterol levels in animal and/or human model.They could improve one or more of the serum lipid profiles,including total cholesterol,triglyceride,low-density lipoprotein cholesterol and high-density lipoprotein cholesterol.Lacticacid bacteria could reduce cholesterol levels by regulating relative gene expression of the absorption and transportation,catabolism and/or synthetic metabolism of cholesterol in vivo.The cholesterol-lowering effect and mechanism of Lactic acid bacteria is strain-specific.The purpose of this paper is to provide a comprehensive overview on the above contents,and to describe its future prospects of current problem.It’s also a reference of cholesterol-lowering lactic acid bacteria for further research.

Lactic acid bacteria;cholesterol;metabolism;regulation;mechanism

Q939.11+7

：B

：1001-2230（2016）02-0032-05

2015-07-31

黑龍江省教育廳面上項(xiàng)目（12531631）；黑龍江中醫(yī)藥大學(xué)?？蒲谢痦?xiàng)目（201104；201316）；黑龍江省自然科學(xué)基金項(xiàng)目（C201233）。

國(guó)立東（1982-），男，副教授，研究方向?yàn)楣δ苄允称放c食品生物技術(shù)。