引用本文
钟港, 陈东. 黄酮类化合物在脂肪代谢中的作用机制研究进展[J]. 动物营养学报, 2022, 34(6): 3483-3494.
ZHONG Gang, CHEN Dong. Research Progress on Mechanism of Flavonoids in Fat Metabolism[J]. Chinese Journal of Animal Nutrition, 2022, 34(6): 3483-3494.
黄酮类化合物在脂肪代谢中的作用机制研究进展
湖南农业大学动物科学技术学院, 长沙 410128
摘要: 近年来, 黄酮类化合物在脂肪代谢中的作用被广泛研究, 大量的体内外试验发现黄酮类化合物具有明显的降脂作用, 是一种天然的调控脂肪代谢物质。本文主要介绍了黄酮类化合物的来源、分类、主要化合物及其与脂肪代谢的关系, 并从miRNAs、肝脏组织腺苷酸活化蛋白激酶(AMPK)、脂肪组织AMPK、有丝分裂克隆扩增(MCE)和神经系统等途径探讨了黄酮类化合物调控机体脂肪代谢的分子机制, 以期为黄酮类化合物的科学应用提供理论依据。
关键词:
黄酮类化合物 脂肪代谢 作用机制
Research Progress on Mechanism of Flavonoids in Fat Metabolism
College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China
Abstract: In recent years, the role of flavonoids in fat metabolism has been widely studied. A large number of in vivo and in vitro experiments have found that flavonoids have obvious lipid-lowering effects and are a natural regulation of fat metabolism. In this paper we mainly discussed the sources, classification, main compounds and their relationship with fat metabolism of flavonoids, and summarized the studies focusing on the molecular mechanisms of fat metabolism regulated by flavonoids through miRNAs, adenosine-activated protein kinase (AMPK) in liver tissue, AMPK in adipose tissue, mitotic clone amplification (MCE) and nervous system, in order to provide theoretical basis for the scientific application of flavonoids.
Key words:
flavonoids fat metabolism mechanism
脂肪的形成是一个复杂的过程，与许多转录因子和脂肪细胞特异性基因表达有关，因此，调控转录因子及相关基因的表达是抑制脂肪沉积的有效途径。自然界中含有5 000多种天然黄酮类化合物，其主要来源于水果、蔬菜和茶叶等[1]。黄酮类化合物可以调控脂肪代谢，研究发现，芹菜素可以通过增加过氧化物酶体增殖物激活受体α(PPARα)和降低胆固醇调节元件结合蛋白1c(SREBP1c)的表达影响脂肪合成[2]；而橙皮苷则通过影响过氧化物酶体增殖物激活受体γ(PPARγ)和3-羟基-3-甲基戊二酰辅酶A还原酶(HMGCR)编码基因的表达来调节脂肪酸和胆固醇代谢进而调控脂肪代谢[3-4]。本文将讨论黄酮类化合物调节机体脂肪代谢的分子机制，总结黄酮类化合物影响机体脂肪代谢的研究进展。
1 黄酮类化合物的来源、分类、主要化合物及其作用黄酮类化合物是一类广泛分布于植物中的酚类化合物，它由2个苯环和1个杂环吡喃酮环组成(图 1)，根据杂环的氧化和饱和状态，可以分为7个亚类：花青素、黄烷醇、黄烷酮、黄酮醇、异黄酮、黄酮和查耳酮[5]。研究表明，黄酮类化合物具有抗氧化、抗菌、抗糖尿病、抗疲劳、抗肥胖、保护肝脏、保护心脏和保护视网膜等多种功能[6-8]。在畜禽饲粮方面，黄酮类化合物主要来源于大麦成熟籽粒[9]、大豆[10]和紫花苜蓿[11]等原料，表 1总结了黄酮类化合物的分类、主要来源、各亚类主要化合物及主要作用[10, 12-28]，为研究黄酮类化合物调节脂肪代谢提供更明确的方向。
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图 1 黄酮类化合物共有化学结构 Fig. 1 Common chemical structure of flavonoids |
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表 1 黄酮类化合物分类、主要来源、主要化合物及其作用 Table 1 Classification, main sources, main compounds and functions of flavonoids |
脂肪代谢对机体健康和畜禽产品质量十分重要，脂肪代谢失衡可能会引起机体出现一系列症状，如肥胖、糖尿病和脂肪肝等，因此，天然产品及其植物化学物质正受到越来越多的关注，对其调节脂肪代谢功效、安全性和效果稳定性抱有很大期望。天然黄酮类化合物已被证明对脂肪代谢有潜在的调控作用，广泛分布于植物界，是食物中最丰富的多酚类化合物[29]。研究者们在细胞水平、小鼠模型、畜禽以及人体上进行了大量试验，发现各类黄酮类化合物均能减少脂肪合成和增加脂肪酸氧化分解，从而调控机体脂肪代谢(表 2)[13, 15-16, 19, 22, 25, 28, 30-65]。
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表 2 黄酮类化合物对脂肪代谢的影响 Table 2 Effects of flavonoids on fat metabolism |
目前，已经对外源营养素调控脂肪代谢的分子机制进行了广泛的研究，其主要包括介导miRNAs表达, 调控腺苷酸活化蛋白激酶(AMPK)途径, 调节有丝分裂克隆扩增(MCE)过程, 影响神经系统、线粒体代谢和G蛋白偶联受体等途径调控脂肪代谢。通过阅读大量文献发现，黄酮类化合物主要通过前4条途径调控机体脂肪代谢，本文主要结合前人试验研究结果，重点介绍黄酮类化合物调控脂肪代谢的这4条主要途径。
3.1 通过介导miRNAs调控脂肪代谢miRNAs是基因组中编码的短双链RNA(约22个核苷酸)，在转录后发挥作用，调节蛋白质的表达，1个miRNA可以有多个靶标，同时作用于调节各种基因转录后的表达和生理过程[66]。脂肪代谢受到miRNAs的调节，研究发现miR-33降低肉毒碱棕榈酰转移酶1(CPT1)mRNA转录进而抑制脂肪酸α氧化[67]，miR-122正向调控SREBP1c和脂肪酸合成酶(FAS)的转录[68]，miR-103和miR-107正向调控胆固醇调节元件结合蛋白1(SREBP1)的表达[69]，进而促进脂肪合成。miRNAs的表达受黄酮类化合物的调控，Su等[70-71]利用油脂诱导的HepG2细胞和高脂饮食诱导的小鼠研究发现，柑橘和荔枝果肉中黄酮类化合物通过下调miR-122间接降低FAS的表达来抑制脂肪合成，下调miR-33直接升高CPT1α和三磷酸腺苷结合盒转运蛋白A1(ABCA1) mRNA的表达进而促进脂肪酸氧化分解，改善脂肪代谢。另外，有研究发现，在小鼠饲粮中添加槲皮素可以下调肝脏中miR-122基因的表达，间接降低了过氧化物酶体增殖物激活受体(PPAR)mRNA水平，从而减少肝脏脂肪沉积[72]。由此可见，黄酮类化合物通过影响miRNAs的表达，影响脂肪代谢相关基因(如CPT1α、ABCA1、FAS和PPAR等)的表达，进而调控机体脂肪代谢。
3.2 通过调节AMPK途径调控脂肪代谢AMPK是一种蛋白激酶，广泛存在于组织器官中，如肝脏、肌肉、脂肪和下丘脑等，通过参与物质代谢的多个环节来维持细胞能量供求平衡，有“能量的感受器”之称。在不同组织器官中，AMPK调控途径有所差异，下面主要从肝脏和脂肪组织中总结黄酮类化合物介导AMPK通路调控脂肪代谢的研究进展。
3.2.1 黄酮类化合物肝脏组织AMPK途径和脂肪代谢肝脏是机体的主要代谢器官，在调节碳水化合物、脂肪和蛋白质代谢方面起着重要的作用[73]，肝脏脂肪代谢失衡会引发肥胖及代谢综合征等一系列疾病。已有研究发现，黄酮类化合物或富含黄酮类化合物的植物提取物能通过激活AMPK通路降低肝脏甘油三酯(TG)和脂肪含量。体内试验发现，槲皮素通过激活肉鸡肝脏中AMPK显著增加PPARα mRNA的表达，同时降低PPARγ和SREBP1c mRNA的表达，进而减少胆固醇生成，增加脂肪氧化分解，加强脂质从肝脏转出，减少脂肪沉积[74]。在老鼠模型中，山楂叶黄酮类提取物通过激活AMPK通路，影响SREBP1c和PPARα mRNA的表达，来改善高脂饮食诱导的非酒精性肝病(NAFLD)大鼠肝脏脂肪变性[75]；而从泡桐花黄酮类提取物通过激活AMPK，能显著降低HMGCR、SREBP1c和FAS表达，同时显著提高CPT1和磷-胰岛素受体底物-1(P-IRS-1)的表达，减少小鼠肝脏中的脂质积累，降低胰岛素抵抗[76]。同时，也有研究者进行了体内外结合试验，发现5-乙酰氧基-6, 7, 8, 3’, 4’-五甲氧基黄酮在体外3T3-L1细胞中，能显著降低TG含量，进一步通过高脂饮食诱导肥胖小鼠体内试验发现，还能减轻高脂血症，降低肝脏TG含量，其分子机制是通过激活肝激酶1(LKB1)-AMPK通路，影响细胞和肝脏中脂肪生成相关蛋白[FAS和磷酸化乙酰辅酶A羧化酶(pACC)]及细胞中相关转录因子SREBP1的表达来抑制脂质积累[77]。
另有研究发现，AMPK通路的激活需要其他因子的介导，Inamdar等[78]研究发现杜荆素(一种天然黄酮类化合物)通过与瘦素受体(LepR)结合激活AMPK通路，下调PPARγ、CCAAT/增强子结合蛋白α(C/EBPα)和SREBP1c来抑制FAS和乙酰辅酶A羧化酶(ACC)的表达，进而抑制脂肪的合成，同时上调PPARα，以增加CPT1α和脂肪甘油三酯脂肪酶(ATGL)的表达，增强脂肪酸氧化和脂肪分解。桑椹乙醇提取物(富含花青素等黄酮类化合物)通过促进小鼠肝脏脂联素受体2(AdipoR2)和胰岛素诱导基因1(Insig1)表达，激活AMPK通路减少肝脏脂肪堆积[79]。总之，在肝脏中，黄酮类化合物先结合特定受体，激活AMPK通路，进而影响脂肪代谢相关基因的表达，调控肝脏脂肪代谢。
3.2.2 黄酮类化合物脂肪组织AMPK途径和脂肪代谢脂肪组织是由白色脂肪、棕色脂肪和米色脂肪3种组织组成的器官[80]，白色脂肪组织(WAT)储存脂肪、分泌瘦素并影响脂质代谢；棕色脂肪组织(BAT)是一种潜在的内分泌器官，影响远处组织的代谢活动以协调全身代谢，对通过解偶联蛋白1(UCP1)增加能量消耗至关要，而UCP1是对抗肥胖的潜在治疗靶点[81]；米色脂肪组织与WAT类似，也具有产热能力[82]，还能预防体重增加和代谢紊乱并促进全身能量平衡[83-84]。研究表明，黄酮类化合物可以诱导WAT褐变，增加能量消耗，抑制高脂肪饮食(HFD)诱导的肥胖和改善代谢状态。Liu等[85]通过小鼠体内试验和3T3-L1细胞体外试验研究发现，异戊二烯基化黄酮类化合物通过激活AMPK通路，诱导WAT褐变和激活BAT产热来预防肥胖。
UCP1是一种BAT特异性的热源蛋白，通过将质子转移到线粒体基质，进行氧化磷酸化与ATP合成解偶联反应，从而促进产热[86]，诱导UCP1的表达有助于减少脂肪堆积。研究发现，补充槲皮素可以预防HFD引起的肥胖和代谢综合征，其分子机制是通过AMPK信号通路上调UCP1，增加PPARα和CPT的蛋白水平，诱导WAT褐变，增加产热，从而促进脂肪氧化分解[87-88]。烟酰胺腺嘌呤二核苷酸(NAD+)-依赖性蛋白脱乙酰酶1(SIRT1)，参与多种组织中的多种代谢途径，特别是参与脂肪和葡萄糖代谢等[89]，AMPK被激活后增加脂肪酸β氧化，改变NAD+/还原型烟酰胺腺嘌呤二核苷酸(NADH)比率，从而刺激SIRT1的表达[90]，进一步通过PPARα和过氧化物酶体增殖物激活受体γ辅激活因子-1α(PGC-1α)增加脂肪酸β氧化，调节脂肪代谢[91]。Sun等[92]研究发现，芹菜素通过AMPK-SIRT1/UCP1调节脂肪酸氧化、WAT褐变和产热，进而调控脂肪代谢。PGC-1α是棕色和米色脂肪细胞中线粒体生物发生、氧化代谢和生热基因表达的关键调控因子[93]，AMPK通路能提高PGC-1α的表达，调控WAT和米色脂肪组织的分化和功能[94]，而木犀草素、白杨素通过激活AMPK/PGC-1α信号通路，促进HFD的WAT褐变和BAT产热[95-96]。
因此，在脂肪组织中黄酮类化合物主要通过AMPK-UCP1、AMPK-SIRT1和AMPK-PGC-1α 3条代谢通路，诱导BAT褐变，促进WAT产热，加速脂肪酸氧化分解，调控脂肪代谢。
3.3 通过调节MCE过程调控脂肪代谢MCE是指细胞周期G1期被阻滞并停止细胞分裂的细胞被周期蛋白和依赖于细胞周期蛋白激酶(CDK)刺激而恢复细胞分裂的阶段[97]，前脂肪细胞需要经过MCE过程才能分化为成熟的脂肪细胞[98]，所以抑制MCE过程是抑制脂肪生成的关键分子生物学因素。黄酮类化合物主要有2种方式抑制MCE过程，其一是通过抑制细胞增殖来抑制MCE过程，如姜黄素和咖啡因[99-100]；其二是通过诱导细胞凋亡抑制MCE过程，进而影响前脂肪细胞成脂分化，如木犀草素A、4, 2’-二羟基-4’, 5’, 6’-三甲氧基查尔酮和7, 8-二羟基黄酮[101-102]。
此外，MCE过程受到相关因子的调节，如，p38丝裂原活化蛋白激酶(MAPK)、细胞外信号调节激酶(ERK)和糖原合成酶激酶-3B(GSK3B)磷酸化后激活CCAAT/增强子结合蛋白β(C/EBPβ)，进而促进PPARγ和C/EBPα基因的表达，使细胞从G1期进入S期，从而启动MCE过程[103]；姜黄素和芹菜素能显著降低C/EBPβ的表达，进而抑制MCE过程，减少脂肪细胞分化[104-105]。另外，抑制细胞周期蛋白和细胞周期蛋白依赖性蛋白激酶(CDKs)的表达也能阻断MCE过程[106]，CDKs激活视网膜母细胞瘤蛋白家族(p130和p107)，解除视网膜母细胞瘤(Rb)对E2启动子结合因子(E2F)的抑制作用，进而激活E2F家族基因转录，使细胞进入S期，启动MCE过程[107]。Lee等[108]研究发现，甘草提取物(富含黄酮类化合物)通过下调细胞周期关键蛋白和CDKs蛋白的表达，使细胞周期阻滞在G1期，从而在早期抑制3T3-L1细胞的MCE阶段。通过对前人研究的总结，黄酮类化合物可能通过抑制相关因子(C/EBPβ、细胞周期蛋白和CDKs)的表达，阻断MCE过程，抑制前脂肪细胞成脂分化，从而减少脂肪生成。
3.4 通过神经调节作用调控脂肪代谢下丘脑是脂肪组织的能量调节中心，通过交感神经系统调控脂肪组织代谢[109]。黄酮类化合物可以通过神经调节发挥调节脂肪代谢的作用。研究发现，黑豆花青素能显著上调大鼠下丘脑γ-氨基丁酸B1受体(GABAB1R)的表达，进而激活蛋白激酶A(PKA)，降低磷酸化cAMP反应元件结合蛋白(CREB)和神经肽Y(NPY)的表达，从而调节采食行为，控制体重[110]；绿茶儿茶素(GTC)通过抑制儿茶酚-O-甲基转移酶(COMT)的活性，激活交感神经系统(SNS)，进而激活PKA，从而增加能量消耗和脂肪酸氧化分解[111]。总之，黄酮类化合物通过神经系统减少摄食行为和增加消耗，进而调控机体脂肪代谢。
4 小结综上可知，黄酮类化合物是潜在调节脂肪代谢失衡和治疗NAFLD等代谢疾病的药物，目前已开展的广泛的体内体外试验研究发现，黄酮类化合物对脂肪代谢具有显著的影响，其主要通过影响miRNAs、AMPK通路、MCE和神经系统等途径影响转录因子及脂肪代谢相关基因的表达，进而调控脂肪代谢(图 2)。黄酮类化合物在肝脏和脂肪组织中的AMPK途径有所区别，总的效应均是控制体重、减少脂肪组织生成和加速脂肪酸氧化分解，进而减少脂肪堆积，预防肥胖。目前对黄酮类化合物进行了较广泛的研究，但仍有许多方面值得进一步深入研究，如筛选减脂效果最佳的黄酮类化合物成分、最佳剂量和最佳服用时长，对畜禽脂肪代谢的影响是否存在部位差异性等；同时，脂肪代谢的分子机制十分复杂，深入探明黄酮类化合物对脂肪代谢影响的分子机制仍是今后研究的重点。本文综述了黄酮类化合物与机体脂肪代谢的关系，通过多角度总结其分子机制，为调节畜禽脂肪代谢以及人体脂肪代谢失衡药物开发提供理论依据。
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GABAB1R：γ-氨基丁酸B1受体gamma-aminobutyric acid B1 receptor；COMT：儿茶酚-O-甲基转移酶catechol-O-methyl transferase；SNS：交感神经系统sympathetic nervous system；PKA：蛋白激酶A protein kinase A；CREB：cAMP反应元件结合蛋白cAMP responsive element binding protein；NPY：神经肽Y neuropeptide Y；ABCA1：三磷酸腺苷结合盒转运蛋白A1 ATP binding box transporter A1；CPT1α：肉毒碱棕榈酰转移酶1α carnitine palmityl transferase 1α；FAS：脂肪酸合成酶fatty acid synthetase；PPAR：过氧化物酶体增殖物激活受体peroxisome proliferator-activated receptor；CDKs：细胞周期蛋白依赖性蛋白激酶cyclin-dependent protein kinases；MAPK：丝裂原活化蛋白激酶mitogen activated protein kinase；ERK：细胞外信号调节激酶extracellular signal-regulated kinase；GSK3B：糖原合成酶激酶-3B glycogen synthase kinase-3B；C/EBPβ：CCAAT/增强子结合蛋白β CCAAT/ enhancer binding protein β；PPARγ：过氧化物酶体增殖物激活受体γ peroxisome proliferator-activated receptor γ；C/EBPα：CCAAT/增强子结合蛋白α CCAAT/ enhancer binding protein α；E2F：E2启动子结合因子E2 promoter binding factor；MCE：有丝分裂克隆扩增mitotic clonal expansion；LepR：瘦素受体leptin receptor；AdipoR2：脂联素受体2 adiponectin receptor 2；Insig1：胰岛素诱导基因1 insulin induced gene 1；AMPK：腺苷酸活化蛋白激酶AMP-activated protein kinase；SREBP1c：胆固醇调节元件结合蛋白1c cholesterol regulatory element binding protein 1c；PPARα：过氧化物酶体增殖物激活受体α peroxisome proliferator-activated receptor α；ACC：乙酰辅酶A羧化酶acetyl-CoA carboxylase；HMGCR：3-羟基-3-甲基戊二酰辅酶A还原酶3-hydroxy-3-methylglutaryl coenzyme A reductase；ATGL：脂肪甘油三酯脂肪酶adipose triglyceride lipase；P-IRS-1：磷-胰岛素受体底物1 phosphorus-insulin receptor substrate 1；UCP1：解偶联蛋白1 uncoupling protein 1；SIRT1：烟酰胺腺嘌呤二核苷酸-依赖性蛋白脱乙酰酶1 nicotinamide adenine dinucleotide-dependent protein deacetylase 1；PGC-1α：过氧化物酶体增殖物激活受体γ辅激活因子-1α peroxisome proliferator-activated receptor γ coactivator-1α；CPT1：肉毒碱棕榈酰转移酶1 carnitine palmityl transferase 1；WAT：白色脂肪组织white adipose tissue；BAT：棕色脂肪组织brown adipose tissue。 图 2 黄酮类化合物调控脂肪代谢通路图 Fig. 2 Diagram of flavonoid regulation of fat metabolism pathway |
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