Hans Journal of Food and Nutrition Science
Vol.04 No.04(2015), Article ID:16311,7 pages
10.12677/HJFNS.2015.44016

The Regulation Mechanisms of Anthocyanins on Lipid Metabolism in Non-Alcoholic Fatty Liver

Fanghang Zhou, Like Zhang, Yan Yang*

Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou Guangdong

Received: Oct. 18th, 2015; accepted: Nov. 6th, 2015; published: Nov. 11th, 2015

Copyright © 2015 by authors and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY).

http://creativecommons.org/licenses/by/4.0/

ABSTRACT

Anthocyanins are types of biological activity of flavonoids compounds. They can contribute to a variety of diseases’ prevention and treatment, including NAFLD and other chronic non-communicable diseases. The effects of anthocyanins through the regulation of lipid metabolism play important roles in prevention, treatment and related aspects in NAFLD. Therefore, we summarized the current research progress on anthocyanins of lipid metabolism in non-alcoholic fatty liver disease, as well as future research perspectives.

Keywords:Anthocyanins, Non-Alcoholic Fatty Liver Disease, Lipid Metabolism

花色苷对非酒精性脂肪肝脂质代谢调控机制的研究进展

周方行,张莉珂,杨燕*

中山大学公共卫生学院营养学系,广东 广州

收稿日期:2015年10月18日;录用日期:2015年11月6日;发布日期:2015年11月11日

摘 要

花色苷是一类具有多种生物活性的黄酮类化合物,它能够对多种疾病起到防治作用,其中包括非酒精性脂肪肝等慢性非传染性疾病。花色苷对非酒精性脂肪肝的脂代谢的调节作用,在该疾病的预防、诊断以及治疗等过程中均起到重要作用,其相关的作用机制更是近年来的研究热点。因此,本文就花色苷对非酒精性脂肪肝脂类代谢中的研究进展进行综述,并提出了今后的研究展望。

关键词 :花色苷,非酒精性脂肪肝,脂代谢

1. 花色苷

花色苷是植物中含有的一类具有活性的化学成分,主要存在于深色浆果、有色薯类、谷类等植物的果皮以及花瓣中,属于黄酮类化合物[1] ,主要食物来源为蓝莓、桑葚、黑米、紫薯等[2] 。目前,国内外对于花色苷的研究着重于膳食花色苷的生理功效,发现花色苷具有多种生物活性,如抗氧化、降血脂、抗肿瘤,抗炎等[3] 。同时还具有改善脂肪肝、视觉功能、大脑功能,抗肥胖、抗糖尿病、抗心血管疾病,抑制肿瘤等生理功能[4] [5] 。同时,目前已有人群研究也证实,通过膳食摄入花色苷可以帮助治疗和改善非酒精性脂肪肝疾病(non-alcoholic fatty live disease, NAFLD) [3] 。

2. 非酒精性脂肪肝

近年来NAFLD的发病率在世界范围内不断的上升,治疗不得当,可发展为肝纤维化、肝硬化并进展为终末期肝病。在NAFLD中,由于脂代谢的异常,将会导致脂肪累积引起肝脏的炎性病变[6] 。当患者脂代谢异常,体内游离的脂肪酸过多时,能够阻断酪氨酸磷酸化的细胞信号,从而出现异常的丝氨酸和苏氨酸磷酸化非信号转导,增加了胰岛素的抵抗,导致肝炎的进一步发生。并且在脂代谢异常的过程中,由于活性氧簇(ROS)等一系列的细胞因子的作用,最终导致了肝细胞结构和功能的改变[7] 。

目前,NAFLD的治疗方案主要为改变生活方式和营养治疗[8] ,也有通过药物进行治疗,如胰岛素增敏剂、抗氧化剂等[9] 。目前通过膳食补充剂对NAFLD进行营养治疗的研究在逐渐增多[10] ,主要通过发挥膳食补充剂抗氧化、抗炎,调节脂质代谢的作用,以及维持肝细胞功能,减缓肝细胞病变,对非酒精性脂肪肝的疾病起到防治作用[3] 。

3. 花色苷对NAFLD的脂代谢调控机制

以往研究发现,花色苷不仅在非酒精性脂肪肝动物模型的研究中,能够表现出维持NAFLD的肝细胞功能以及功能的完整性的作用[11] ,而且在临床人群研究实验中,也已经有足够的证据证明,花色苷提取物作为治疗制剂,能够有效的降低NAFLD疾病进展中肝炎的临床生化评价指标[12] ;且越来越多研究认为通过膳食补充花色苷,能够改善高胆固醇高脂饮食引起的肝损伤,对于NAFLD的疾病以及并发症起到预防作用[13] 。

花色苷具体在NAFLD体内的代谢途径,以及作用机制近几年更是国内外学者的研究热点,例如,花色苷可以作用于不同的信号通路,与有丝分裂原活化的蛋白激酶,核因子κB,AMP活化的蛋白激酶蛋白和Wnt/β-cateni等相互作用,以及一些关键的细胞过程,如细胞周期,细胞凋亡,自体吞噬等代谢所涉及的过程,并对这些过程产生有益的影响,为未来相关的疾病的改善提供治疗的可能[14] 。目前主要认为,花色苷对于NAFLD的防治作用,主要通过花色苷对于脂代谢途径的调节[15] ,其主要机制包括降低NAFLD患者体内甘油三酯、胆固醇的沉积,增加脂质的消耗和排泄以及作用于其他相关的作用信号通路。

3.1. 降低脂类的沉积

脂类包括脂肪和类脂,在NAFLD中,肝脏代谢紊乱是疾病发展至脂肪肝的重要病理过程。通过动物实验证明,花色苷能够抑制NAFLD患者的体重和脂肪增长[16] 。虽然花色苷在对脂质的积累过程的影响中的脂肪合成的转录因子调控靶点和相关机制尚未确定,但是花色苷在调节NAFLD患者的脂类代谢中却起到了非常重要的作用。而对于花色苷在NAFLD中脂代谢的研究中,主要研究花色苷降低脂类在体内的沉积;其中脂类的研究中,甘油三酯以及胆固醇的代谢经常被作为研究重点。

3.1.1. 降低甘油三酯的沉积

甘油三酯(triglyceride, TG)分布在体内各大器官和组织中,甘油三酯的代谢过程属于脂类代谢主要的代谢过程。Lee B等[17] 通过花色苷对脂肪合成通路的3T3-L1脂肪细胞分化过程中影响的研究,认为花色苷能够降低甘油三酯在脂肪细胞分化中的作用,并降低甘油三酯的积累。

花色苷抑制甘油三酯沉积的作用机制主要可分为以下几方面(如图1)。一方面,花色苷通过降低脂肪合成转录因子的调控基因,如肝X受体α蛋白,胆固醇调节元件结合蛋白-1c [18] ,过氧化物酶体增殖物激活受体α [19] ,CCAAT增强子结合蛋白α [20] ,从而抑制了脂质在肝脏中的过氧化以及沉积[21] 。其中主要作用以花色苷能够下调胆固醇调节元件结合蛋白-1c(SREBP-1c)和过氧化物酶体增殖物激活受体α(PPARα)两者的活性为主,可阻断IL-1β和TNF-αmRNA的增加,并且抑制脂质过氧化和过氧化氢酶的mRNA表达[22] 。同时,还有研究指出花色苷提取物能够增加骨骼肌中PPAR的活性,并且早期摄入花色苷提取物后,可发现PPAR的表达在腹部脂肪组织增加[19] ,从而增加脂质的过氧化,增加脂肪的分解,以及葡萄糖的代谢[23] 。

另一方面,花色苷在抑制脂肪合成转录因子的靶基因中,还可抑制脂肪酸合酶蛋白的表达,硬脂酰辅酶A去饱和酶的活性以及激活腺苷酸AMP激活蛋白(AMPK),从而抑制乙酰辅酶A羧化酶α的活性[16] [24] 。在肝脏代谢紊乱中,AMP蛋白激酶能通过调节下游的乙酰辅酶A羧化酶(ACC)和肉碱棕榈酰转移酶1(CPT-1)通路控制肝脏脂代谢[24] 。因此,根据以上信息,花色苷通过抑制脂肪细胞的相关转录因子的活性,调控脂肪形成累积过程,有效的抑制了脂质在肝脏中的蓄积[17] 。

除以上主要研究的机制以外,还有研究认为,通过饮食摄入的花色苷能够抑制肝脏甘油-3-磷脂酰基转移酶1(mtGPAT1)的活性[25] ,并在线粒体外膜中存在,进而抑制了肝脏的脂肪变性,调节了脂肪的代谢;以及花色苷还可以降低3-羟基-3-甲基-戊二酰辅酶A还原酶(HMGCoR)、脂肪细胞特异性脂肪酸结合蛋白(A-FABP)、以及胆固醇调节元件结合蛋白-2(SREBP-2)的活性[16] ,然后下调其下游的代谢途径进而降低脂肪的沉积,这对于肥胖以及NAFLD都起到了非常好的预防效果。

然而,值得注意的是,除以上普遍较为认可的观点以外,也有研究[16] 认为花色苷增加了PPAR-α的活性,并且也有研究提出相反的观点,如Vauzour D等[26] 通过研究认为饮食中的花色苷的摄入对于体内n-3多不饱和脂肪酸的分布并没有明显的影响,并指出这与花色苷能够对于组织脂肪酸产生有益的作用是不相符合的。

3.1.2. 降低胆固醇的沉积

研究指出,通过植物花色苷提取物能够减缓NAFLD的发展,降低肝脏脂肪的累积、炎症以及纤维

Figure 1. The mechanisms of anthocyanins decreasing the triglycerides in NAFLD

图1. 花色苷在NAFLD中降低甘油三酯的作用机制

化,并认为以上作用可能与花色苷降低了肝内自由胆固醇的累积和结晶的效果有关[15] 。其减少肝内胆固醇的可能机制为:花色苷增加胆汁酸的合成[27] 和粪甾醇排泄,以及增加低密度脂蛋白受体(LDLR)、3羟基3甲基戊二酸辅酶A还原酶(HMGCR) [28] 从而降低肝内胆固醇的积累[29] 。同时补充花色苷可以提高与高密度脂蛋白(HDL)相关的对氧磷酶1的活性从而降低胆固醇的沉积[30] 。

除此之外,花色苷还降低血浆中游离脂肪酸(FFA)的水平、抑制胰脂肪酶的活性,进而预防肥胖以及NAFLD [31] ,并且还降低了肝内游离胆固醇的水平。还有研究认为花色苷能够降低胆固醇的吸收,并且下调肠道中NPC1L1,ACAT-2,MTP,和ABCG 8等基因的表达[32] 。因此,花色苷对于NAFLD的预防以及抑制脂类累积都起到良好的辅助作用[15] 。

3.2. 增加脂质的消耗与排泄

花色苷对于脂代谢途径中,除了减少脂类的聚集以外,还通过增加脂质的消耗以及排泄,从而达到调节脂代谢紊乱的目的。花色苷可通过作用于细胞凋亡的通路,对脂肪的代谢以及肝细胞功能进行调节[11] ,减少脂质在肝脏中的过氧化,同时增加肝脏中的抗氧化酶系统[33] 。尤其是亚型C3G能够减少氧化应激,并减弱小鼠的非酒精性脂肪肝的肝炎,维持NAFLD中肝细胞的功能[11] 。其主要的机制为花色苷调节了线粒体的功能,激活PI3K蛋白激酶的通路[11] ,以及降低c-JunN末端激酶的活性[11] ,从而增加了脂肪酸在肝脏中的分解代谢,同时又保护肝脏不受到脂质过氧化的损伤;也有研究认为花色苷增加盲肠的发酵作用,从而增加脂质了的排泄[34] 。

除此之外,由于过氧化物酶PPAR以及核转录因子Nrf2在氧化应激中的重要作用,也有研究认为花色苷通过激活PPRA-Nrf2系统,打乱了在脂质代谢综合症中过氧化的基因,改善相应的病理情况,增加了脂肪的代谢[35] 。

3.3. 其他机制

除以上提及的主要研究的机制以外,还有通过研究蛋氨酸–胆碱缺乏饮食导致的非酒精性脂肪肝的模型,认为可能花色苷通过影响AMP/PCG-1α信号通路起作用 [13] 。同时还有研究指出花色苷能够改善由于代谢综合征中脂肪肝和葡萄糖的代谢[36] ;增加了脂肪细胞对胰岛素酶的敏感性[37] ,从而达到降低脂肪的沉积,起到对NAFLD的保护作用。

4. 结论与展望

综上所述,花色苷对NAFLD脂代谢过程中,通过降低脂类的沉积,增加脂类的消耗和排泄,从而在NAFLD的预防以及治疗等过程中有重要的作用。但是目前国内外对花色苷在非酒精性脂肪肝脂代谢作用机制的研究中多通过对不同的浆果提取花色苷作为研究材料,而不同亚型的花色苷其生理活性所起到的效果值得商榷,如有研究认为不同的水果中提取的物质其黄酮类化合物的排泄以及吸收和抗胆固醇作用是不同的[38] 。同时花色苷对体内部分调节因子的作用还存在争议,且由于花色苷的特殊的饮食摄入方式,花色苷与其他物质结合[39] 时的协同作用可影响结果的可靠性。因此,因此在单独研究时,也应当考虑到其他化学物的协同效应[40] ,予以控制偏倚,相关的研究结果还值得更深入的人群或动物实验研究探讨和标准化。

文章引用

周方行,张莉珂,杨 燕. 花色苷对非酒精性脂肪肝脂质代谢调控机制的研究进展
The Regulation Mechanisms of Anthocyanins on Lipid Metabolism in Non-Alcoholic Fatty Liver[J]. 食品与营养科学, 2015, 04(04): 116-122. http://dx.doi.org/10.12677/HJFNS.2015.44016

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