食品功能性成分降血脂作用機理研究進展

鄒莉芳，沈以紅，黃先智，丁曉雯,*（.西南大學食品科學學院，重慶市農產品加工重點實驗室，重慶 40075；.家蠶基因組生物學國家重點實驗室，重慶 40075）

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食品功能性成分降血脂作用機理研究進展

鄒莉芳1，沈以紅2，黃先智2，丁曉雯1,*
（1.西南大學食品科學學院，重慶市農產品加工重點實驗室，重慶 40071
5；2.家蠶基因組生物學國家重點實驗室，重慶 400715）

摘 要：高脂飲食的攝入打破了體內脂質代謝平衡，是目前高脂血癥患者數量急劇增加的原因之一。具有降血脂功效的食品很多，其功能成分主要為膳食纖維、多糖類、多酚類、生物堿類、皂苷等。本文綜述了食物中常見的具有降血脂作用成分的功效及其作用機制的最新研究進展，為降血脂研究及功能食品的開發提供參考。

關鍵詞：降血脂；膽固醇；脂肪酸；甘油三酯

引文格式：

鄒莉芳,沈以紅,黃先智,等.食品功能性成分降血脂作用機理研究進展[J].食品科學,2016,37(5):239-244.

ZOU Lifang,SHEN Yihong,HUANG Xianzhi,et al.Progress in research on hypolipidemic mechanisms of functional food components[J].Food Science,2016,37(5):239-244.(in Chinese with English abstract)DOI:10.7506/spkx1002-6630-201605042.http://www.spkx.net.cn

心血管疾病（cardiovascular disease，CVD）是全世界死亡的首要原因，而高脂血癥是導致心血管疾病最重要的危險因素之一。高脂血癥是指血漿總膽固醇（total cholesterol，TC）、甘油三酯（triglyceride，TG）和低密度脂蛋白膽固醇（low-density lipoprotein cholesterol，LDL-C）過高，高密度脂蛋白膽固醇（high-density lipoprotein cholesterol，HDL-C）偏低[1-2]。血脂的高低與膳食習慣和身體代謝能力關系密切，減少飽和、反式脂肪酸和膳食膽固醇的攝入，增加降血脂保健食品攝入都有助于降低血脂[3]。研究發現，有許多食品的功能性成分具有降血脂功效[4]。本文總結降血脂功能食品的最新研究成果，就食品中存在具有降血脂功能的成分及其降血脂機制進行綜述，為降血脂功能食品的開發提供參考。

1　脂質代謝調控機制

1.1膽固醇代謝平衡機制

人體膽固醇的來源主要是從食物中獲取和體內合成，體內膽固醇的平衡主要受小腸吸收、內源性合成和在肝臟的轉化、排泄的調控[1]。膽固醇吸收至少由C型尼曼-匹克蛋白（Niemann-pick protein C1，NPC1L1）和兩種ATP結合盒式蛋白G5/G8（ATP-binding cassette proteinG5/G8，ABCG5/G8）調控，前者為流入轉運蛋白，后者為流出轉運蛋白，在小腸和肝臟細胞中膽固醇平衡是通過NPC1L1流入和ABCG5/G8流出控制的[5]。過氧化物酶體增殖物激活受體-δ（peroxisome proliferator activated receptor-δ，PPAR-δ）與配體結合激活后，可以通過上調ATP結合盒式蛋白A1的表達提高HDL水平[6]，通過降低小腸NPC1L1的表達減少膽固醇的吸收[7]，PPAR-δ激活后還可以增加脂肪酸的β-氧化[8]。

在人血漿中，膽固醇酯轉運蛋白（cholesteryl ester transfer protein，CETP）是從HDL向LDL和極低密度脂蛋白（very low density lipoprotein，VLDL）傳送膽固醇酯[9]。HDL-C B族Ⅰ型清道夫受體將HDL-C運送至肝臟或類固醇生成器官；LDL-C受體將LDL-C從循環中除去[10-11]。3-羥基-3-甲基戊二酰輔酶A還原酶（3-hydroxy-3-methyl glutaryl coenzyme A reductase，HMGR）是體內合成膽固醇的限速酶，固醇調節元件結合蛋白2（sterol-regulatory element binding protein 2，SREBP-2）控制LDL-C受體和HMGR的轉錄，當肝細胞膽固醇水平低，通過轉錄因子SREBP-2上調HMGR的表達；SREBP-2可激活LDL受體的表達，LDL受體升高將有利于血漿膽固醇含量的下降[12-13]。

膽固醇-7α-羥化酶（cholesterol-7α-hydroxylase，CYP7A1）是啟動肝臟膽固醇合成膽汁酸途徑的關鍵調節點[14]。肝臟中膽汁酸含量較高時，通過激活法尼醇X受體（farnesoid X receptor，FXR）反饋抑制CYP7A1的轉錄[15]；肝X受體（liver X receptor，LXR）可促進CYP7A1的轉錄，加速膽汁酸的生成[16]。

MicroRNA-122（miR-122）可影響與機體膽固醇和脂肪酸代謝相關的脂肪酸合成酶（fatty acid synthetase，FAS）、乙酰輔酶A羧化酶1（acetyl-CoA carboxylase 1，ACC1）、HMGR和SREBP-1c的活性與含量，從而影響脂肪酸和膽固醇合成[17-18]。miR-33位于SREBP基因的內含子中，同時還調控另一膽固醇轉運體ATP結合盒式蛋白G1，在調節脂質代謝平衡中起重要作用[19]。

綜上所述，在膽固醇的代謝平衡中，通過轉運蛋白調節肝臟和小腸膽固醇平衡；通過調節SREBP-2 mRNA的表達抑制HMGR的活性來控制體內膽固醇的合成；通過調節FXR和LXR的活性，抑制CYP7A1的活性和mRNA的表達，降低膽汁酸的合成，阻斷膽汁酸肝腸循環，減少肝細胞膽固醇的來源，進而降低體內膽固醇水平。

1.2甘油三酯和脂肪酸代謝平衡機制

在肝臟中SREBP-1c基因調控脂肪的重新合成，由胰島素以及內質網應激反應激活[20-21]。SREBP-1c調節參與脂肪酸和甘油三酯基因的轉錄合成，如ACC、FAS和硬脂酰CoA去飽和酶（stearoyl CoA desaturasescd，SCD）的合成[22-23]。AMP蛋白激酶（activated protein kinase，AMPK）通過抑制SREBP-1c，控制整個脂肪生成途徑或通過直接抑制FAS活性降低脂肪酸的合成，降低肝臟組織的甘油三酯水平，促進脂肪酸的β-氧化；還可以通過調節SCD-1和酰基輔酶A氧化酶（acyl-CoA oxidase，COX）的表達起到降血脂的作用[24]。線粒體外膜上的肝臟肉毒堿棕櫚酰轉移酶1A（carnitine palmitoyltransferase 1A，CPT1A）是脂肪酸氧化限速酶，可加速脂肪酸氧化，降低肝臟TG水平[25]。PPAR-α基因在肝、腎和肌肉中高度表達，直接調控與脂肪酸β-氧化、膽固醇分解有關的基因[26]。脂肪的消化和吸收需要胰脂肪酶的參與，抑制胰脂肪酶的活性可以抑制脂肪的分解；脂蛋白脂肪酶（lipoprotein lipase，LPL）可以催化甘油三酯水解成甘油和脂肪酸，繼續氧化提供能量[27]。

在甘油三酯和脂肪酸代謝平衡中，通過調節AMPK信號通路中的信號因子（SREBP-1c、ACC、CPT1A）的活性而達到抑制肝臟中脂肪酸合成，促進脂肪酸氧化的作用；通過對與脂肪消化吸收有關的酶活性的調節來抑制脂肪在體內的積累，達到降低血脂的目的。

2　功能性降脂成分的作用機理

天然食物中含有大量具有降血脂功能的活性成分，不同活性成分的降血脂機制有所不同，下文對常見的幾種活性成分的降血脂作用機理進行歸納總結。

2.1膳食纖維

膳食纖維是國際上公認的第七營養素[28]。研究表明，可溶性膳食纖維可預防和治療心腦血管疾病[29]。燕麥[30]、蘋果果膠[31]、歐車前水溶性纖維[32]和羥乙基甲基纖維素[33]等膳食纖維都具有降血脂的功效。

膳食纖維的降血脂機制主要有：通過減少肝臟膽固醇的生成，促進肝臟膽固醇轉化成膽汁酸而降低肝臟中的膽固醇含量。Tong Litao等[34]通過給倉鼠喂飼麥麩阿拉伯木聚糖，發現其可通過下調HMGR活性和提高CYP7A1的活性，增加丙酸和短鏈脂肪酸的濃度，從而降低膽固醇的合成和增加膽固醇的排泄。Kim等[35]用添加了質量分數為5%的羥丙基甲基纖維素（hydroxypropyl methylcellulose，HPMC）的大麥和燕麥面包喂飼敘利亞金黃地鼠，與對照組比較，發現富含HPMC的大麥和燕麥面包可通過下調SREBP-2的mRNA表達來抑制HMGR的mRNA表達，從而降低血或肝臟中的膽固醇或甘油三酯。

膳食纖維的降血脂機制還可以是調控與脂肪酸氧化相關酶的活性、誘導脂肪酸氧化、降低肝臟TG水平來實現。Kim等[36]采用添加62.9%的發酵大豆纖維喂食C57BL/6J小鼠12 周，與對照組比較，發現實驗組小鼠與脂肪酸氧化相關的B類清道夫受體CD36基因的表達、酰基輔酶A合成酶（acyl-CoA synthetase，ACS）、CPT1A 和COX1的活性顯著上調。Zhang Wei等[37]用添加3%的殼聚糖納米粉末喂飼Sprague-Dawley（SD）大鼠6 周，與對照組相比，顯著提高了實驗組大鼠肝臟LPL和肝脂酶（hepatic lipase，HL）的活性，促使VLDL中的TG水解為甘油和脂肪酸，具有良好的降血脂活性。

2.2多糖

多糖已被廣泛研究作為一個新來源的膳食補充劑和功能性食品原料。研究發現，大棗多糖[38]、海帶多糖[39]、南瓜多糖[40]、當歸多糖[41]、條斑紫菜多糖[42]等多糖都具有降血脂的功效。

活性多糖降血脂可以通過抑制膽固醇合成、阻斷膽固醇的肝腸循環、降低血漿膽固醇含量來實現。Wang Hong等[43]從秋葵中提取多糖喂飼雄性C57BL/6小鼠，結果表明秋葵多糖通過上調CYP7A1的mRNA表達，下調SREBP1c和FAS的mRNA表達，從而降低總膽固醇和甘油三酯，增強糞便膽汁酸排泄，達到了降血脂的功效。Hoang等[44]研究了從礁膜中提取的硫酸多糖的降血脂機理，發現硫酸多糖的降血脂功能是通過抑制HMG-CoA還原酶的表達和CYP7A1的活性，增加LDL受體的表達，從而阻斷體內膽固醇的合成，抑制膽汁酸和膽固醇的吸收來實現的。

多糖的降脂機理還可以通過調控脂肪細胞分化、抑制脂肪酸分解相關酶的活性、促進脂肪酸氧化、清除體內多余的自由基抑制脂質過氧化來實現。Yu Chenhuan等[45]認為從金櫻子中提取的多糖可能是通過上調PPAR-γ和高脂血癥大鼠的LPL的mRNA表達而達到抑制肝脂質積聚，增加脂質的抗氧化活性的作用。Yang Junxuan等[46]喂飼新西蘭兔0.8 mL/kg黃精多糖8 周，經過H2O2誘導，與對照組相比，實驗組新西蘭兔的內皮細胞的丙二醛含量下降，超氧化物歧化酶活性上升。

2.3多酚

多酚又稱“植物單寧”，包括苯酚酸和黃酮類化合物，主要存在于植物的根、皮、葉和果實中，有很強的生物活性。研究發現，石榴多酚[47]、葡萄多酚[48]、可可多酚[49]、茶多酚[50]等多酚類物質都具有降血脂的功效。

Park等[51]用富含多酚的紅殼皮糯米（含質量分數為2%的高膽固醇）喂飼小鼠12 周，發現該物質可以通過抑制酰基輔酶A膽固醇酰基轉移酶-2（acyl-CoA cholesterol acyltransferase-2，ACAT-2）、HMG-CoA還原酶和SREBP-2的mRNA的表達來抑制肝膽固醇合成，并通過增強CYP7A1和甾醇12α-羥化酶（sterol 12α-hydroxylase，CYP8B1）的表達來促進體內肝膽固醇的降解，從而降低體內膽固醇的含量。Baselga等[52]通過喂飼肥胖大鼠花青素，發現花青素可以使miR-33a和miR-122的表達正常化，miR-33和miR-122可以反饋抑制調節miR-33a的靶基因ABCA1的水平和miR-122的靶基因FAS和PPAR/δ的表達，從而減少肥胖大鼠肝臟膽固醇含量和減少脂肪酸合成。佛手瓜芽體的水提取物經高效液相色譜法（high performance liquid chromatography，HPLC）分析證明其主成分為咖啡酸和橙皮素，Yang Monyuan等[53]研究發現佛手瓜芽體的水提取物通過增強AMPK的活性和激活PPAR-α和CPT-I的mRNA表達來減少肥胖大鼠體內脂質的積累。Jia Sheng等[54]給KK-Ay糖尿病小鼠喂飼50 mg/kg胡柚中提取的新橙皮苷6 周后，發現新橙皮苷可抑制肝臟中脂質的積聚，提高小鼠肝臟的AMPK水平，顯著抑制SCD-1和FAS的mRNA表達，顯著提高COX的mRNA表達。

2.4生物堿

生物堿是存在于自然界中的一類含氮的堿性有機化合物。經大量研究發現生物堿具有降血脂作用。Wu Hao等[55]喂飼金黃地鼠藥根堿70.05 mg/kg，4 周后發現其可以顯著降低金黃地鼠體質量，并且顯著降低TC、TG和LDL-C水平，升高HDL-C水平，此外，藥根堿可顯著降低血液膽汁酸的含量，增加糞便中總膽汁酸（total bile acid，TBA）排泄。

Bao Lidao等[56]采用10 mg/kg胡椒堿喂飼大鼠2 周，發現胡椒堿可以下調HMGR的mRNA表達、上調卵磷脂膽固醇酰基轉移酶（lecithin cholesterol acetyl transferase，LCAT）mRNA的表達，從而提高HDL-C的水平，降低膽固醇的合成。Ning Na等[57]將黃藤素添加到高脂飲食中喂養倉鼠，發現黃藤素可以通過上調LDL-R和CYP7A1 的mRNA表達、下調頂膜鈉依賴性膽鹽轉運體（apical sodium dependent bile acid transporter，ASBT）的mRNA和蛋白質表達，以促使膽固醇和膽汁酸排出體外。

1-脫氧野尻霉素（1-deoxynojirimycin，1-DNJ）是一種重要的生物堿，主要來源于桑葉、微生物以及人工合成。Do等[58]研究發現從枯草芽孢桿菌中分離得到的1-DNJ可以使小鼠肝臟中的乙酰輔酶A羧化酶（acetyl-CoA carboxylase，AAC）和FAS的mRNA表達明顯降低，而PPAR-γ的轉錄輔助活化因子（PPAR-γ coactivator-1，PGC-1）和P-AMPK/AMPK的mRNA表達升高，表明1-DNJ可能是通過調節參與脂肪生成和線粒體功能的肝基因的表達而達到降血脂的功效。曾藝濤等[59]研究發現，1-DNJ可通過降低雌性小鼠的ACC活性和游離脂肪酸含量以及提升脂聯素含量來抑制脂肪酸合成；通過提升雄鼠的CPT-1活性和脂聯素含量，降低游離脂肪酸含量來促進脂肪酸分解，減少脂肪的積累。

2.5皂苷

皂苷廣泛存在于植物體中，也少量存在于海星和海參等海洋生物中，對防治心血管疾病、降血脂有重要的作用。非洲茄子皂苷[60]、太白楤木皂苷[61]等皂苷成分具有顯著的降血脂、抗脂質過氧化作用。

皂苷可以通過抑制肝臟膽固醇的合成、增加血漿膽固醇的流出起到降低血漿膽固醇水平的作用。Ma Weilie 等[62]經研究發現，甲基原薯蕷皂苷可以抑制THP-1巨噬細胞SREBP1c和SREBP2的轉錄，增加LDL受體和ABCA1 的mRNA表達，促進膽固醇的流出。Sho等[63]研究了苦瓜總皂苷的降血脂作用，研究發現苦瓜總皂苷可通過上調CYP7A1的表達和下調FXR的表達進而促膽固醇向膽汁酸轉化以及促進膽汁酸從腸道排泄。

皂苷還可以調控脂質代謝相關酶、增強脂質的抗氧化能力來發揮降脂作用。Wang Yuming等[64]通過喂飼肥胖小鼠海參皂苷7 周，對小鼠肝臟脂質代謝相關酶活性進行測定，發現海參皂苷具有抑制FAS、葡萄糖-6-磷酸脫氫酶、蘋果酸酶等脂質相關合成酶活性的作用。

2.6其他

He Shan等[65]發現深海水中含有大量的礦物質以及微量元素具有降低血脂的功效，它們主要是通過激活AMPK來降低肝細胞的脂質含量，從而抑制膽固醇和脂肪酸的合成。此外，還上調LDL受體、SREBP-2和CYP7A1的mRNA表達，從而降低LDL水平和增加膽固醇的流出。

Rashid等[66]將從棕櫚油中富集得到的生育三烯酚作為膳食補充劑喂飼高脂飲食大鼠，與對照組相比可顯著降低TC、TG和LDL-C水平，并且降低了氧化低密度脂蛋白的水平，從而抑制了動脈粥樣硬化的發生。

紫蘇油中含有豐富的α-亞麻酸，Zhang Tao等[67]發現喂飼紫蘇油的大鼠與對照組相比，顯著降低TC、TG的水平，增加肝臟中PPAR-α、CPT1A的mRNA表達，促進肝脂肪酸的氧化；上調了血清中SREBP-1、FAS和ACC的mRNA表達，顯著降低血清脂質并抑制肝脂肪酸合成。

3　結 語

隨著天然食物中的活性成分成為營養研究和藥物開發的熱點，研究這些活性成分的生物活性及作用機制可以大大促進其開發應用，能顯著提高天然食物的附加值。多項研究顯示，利用這些活性成分開發的功能性食品可作為膳食干預或膳食補充劑，預防人類疾病，尤其是高血脂、高血壓等心血管慢性疾病，促進人體健康。

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Progress in Research on Hypolipidemic Mechanisms of Functional Food Components

ZOU Lifang1,SHEN Yihong2,HUANG Xianzhi2,DING Xiaowen1,*
(1.Chongqing Key Laboratory of Agricultural Product Processing,College of Food Science,Southwest University,Chongqing 400715,China; 2.State Key Laboratory of Silkworm Genome Biology,Chongqing 400715,China)

Abstract:Increased intake of high-fat diets,disturbing the metabolic balance of liposomes in the body,is one of the major reasons for the dramatic increase in the prevalence of hyperlipidemia.On the other hand,many foods exert lipid-lowering effects through their functional components such as dietary fiber,polysaccharides,polyphenols and steroidal saponins and alkaloids.Herein,we review the latest progress in the study of the hypolipidemic effect and mechanisms of functional food components,aiming to provide a reference for future development and utilization of hypolipidemic natural products.

Key words:hypolipidemic; cholesterol; fatty acid; triglycerides

中圖分類號：TS201.4

文獻標志碼：A

文章編號：1002-6630（2016）05-0239-06

DOI:10.7506/spkx1002-6630-201605042 10.7506/spkx1002-6630-201605042.http://www.spkx.net.cn

*通信作者：丁曉雯（1963—），女，教授，博士，研究方向為食品安全與功能食品。E-mail：xiaowend@sina.com

作者簡介：鄒莉芳（1991—），女，碩士研究生，研究方向為食品安全與質量控制。E-mail：zoulifang526@163.com

基金項目：國家現代農業（蠶桑）產業技術體系建設專項（CARS-22）

收稿日期：2015-06-25