法尼醇X受体对甘油三酯的代谢调节

摘要

法尼醋X受体(farnesoid x receptor, FXR)属于配体依赖的核转录因子, FXR主要在肝脏、肠道、肾脏、肾上腺等表达, FXR因其可被内源性配体胆汁酸激活, 故又称胆汁酸受体, 他是孤儿核受体超家族中的一员. 被内源性配体胆汁酸激活后的FXR在甘油三酯(triglyceride, TG)代谢过程中起着重要作用, FXR可通过调控与TG代谢的关键酶、脂蛋白和相应受体, 从而使肝脏及循环血液中TG含量达到稳态平衡, 本文就FXR对TG的代谢调节作一综述.

关键词: 法尼醇X受体; 甘油三酯; 脂蛋白; 酶

Regulation of triglyceride metabolism by the Farnesoid X receptor

Dao-Tong He, Jun-Ming Chen, Bing Wang

Dao-Tong He, Jun-Ming Chen, Bing Wang, School of Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai 200233, China

Supported by: the Traditional Chinese Medicine Science and Technology Fund of Shanghai Municipal Health Bureau, Nos. 2008L011A and 2010L060A; the Scientific Research Fund Project of Shanghai Institute of Integrated Traditional and Western Medicine, No. zxyk-1205.

Correspondence to: Bing Wang, Chief Physician, Shanghai Sixth People's Hospital of Shanghai Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200233, China. bingliver@163.com

Received: September 28, 2012
Revised: November 22, 2012
Accepted: December 20, 2012
Published online: December 28, 2012

Abstract

Farnesoid x receptor (FXR) is a ligand-dependent nuclear transcription factor, belonging to the nuclear receptor superfamily. It is activated by bile acids (BAs) and is expressed in the liver, intestine, kidney, and adrenal gland. Upon activation by endogenous ligand (BAs), FXR can regulate triglyceride (TG) metabolism by modulating the activity of related enzymes, lipoprotein and receptors, and maintaining the balance between the contents of TG in the liver and circulation. This review aims to elucidate the regulation of triglyceride metabolism by FXR.

Key Words: Farnesoid X receptor; Triglyceride; Lipoprotein; Enzymes

0 引言

高甘油三酯血症(hypertriglyeeridemia)是引起脂肪肝、代谢综合征(metabolic syndrome, MS)及冠心病(coronary heart disease, CHD)的独立危险因素之一[1-4]. 因此, 研究甘油三酯(triglyceride, TG)代谢机制对防治脂肪肝、MS和CHD有重要意义. 经研究证实[5,6], FXR在调控TG代谢中发挥重要作用. Sinal等[6]给予FXR基因敲除小鼠高脂饮食后发现TG含量明显高于对照组, 给予FXR激动剂后TG含量明显较对照组明显降低. FXR因其可被内源性配体胆汁酸激活, 故又称胆汁酸受体, 他是孤儿核受体超家族中的一员[7]. FXR主要在肝脏、肠道、肾脏、肾上腺、脂肪组织和心脏等表达[8]. 配体激活后的FXR对TG的代谢调节是通过调控TG代谢中的关键酶、脂蛋白和相应受体等来实现的.

1 FXR-SHP-SREBPlc-FAS-TG通路

FXR由胆汁酸激活后可激活小异二聚体伴侣分子(small heterodimer partner, SHP)的表达, SHP是一种抑制性核受体[9,10]; 甾醇调节元件结合蛋(stero1 regulatory element binding proteins, SREBP-s)是一类分布于内质网和核膜上的膜连接蛋白, 有3种同工型: SREBP-la、 SREBP-lc和SREBP-2, 龋齿类动物和人类的肝脏中以SREBP-lc为主, SREBP-lc是一类调控TG和脂肪酸的合成、胆固醇的合成、低密度脂蛋白胆固醇(low-density lipoprotein, LDL)代谢相关基因表达的转录因子. 被FXR激活后的SHP通过抑制LXR的活性下调SREBP-lc的表达, 脂肪酸合酶(fatty acid synthesis, FAS)的活性间接的被抑制, 最终使血浆中TG含量减少[11,12].

2 FXR-PXR-PPARα-β氧化-TG通路

FXR可通过调控过氧化物酶体增殖物激活受体-α(peroxisome prolirerator-activated receptor α, PPAR-α)的活性, 使乙酰辅酶A合酶(acyl coasynthetase, ACS)、肉碱转移酶Ⅰ(carnitine palmitoyl transferase-Ⅰ, CPT-Ⅰ)及脂蛋白脂酶(lipoprotein lipase, LPL)的活性增强, 来调节胆汁酸的合成, 最终降低血浆TG的水平[13]. PPAR激动剂如非诺贝特通过促进脂肪酸在肝脏、肾脏及骨骼肌中的氧化, 降低血浆TG水平. PPAR-α是一种激素激活核受体, 其功能与脂肪酸氧化密切相关[14,15]. PPAR-α高表达于具有丰富线粒体和β氧化活性的骨骼肌组织中[16]. PPAR-α主要在肝脏表达, 被配体激活后, 可引起ACS、CPT-Ⅰ、LPL的转录增强. 其中CPT-Ⅰ是脂酸β氧化的限速酶, 其表达增加, 可增强脂肪酸的氧化代谢, 具有对抗肝脂肪变、延缓脂肪肝形成的作用[17]; LPL是清除血浆脂蛋白中所含TG的限速酶, 属于丝氨酸活性酶类, 在极低密度脂蛋白胆固醇(very low density lipoprotein cholesterol, VLDL-C)和乳糜微粒(chylomicron, CM)的代谢中有重要的作用, 在LPL作用下, CM和极低密度脂蛋白(very low density lipoprotein, VLDL)颗粒核心处的TG不断水解, 导致颗粒表面磷脂和未酯化胆固醇过剩并转移至高密度脂蛋白(high-density lipoprotein, HDL), 从而使CM和VLDL分别衍变成CM残体和中密度脂蛋白(intermediate-density lipoprotein, IDL), 促进CM和VLDL-C的代谢, 给予小鼠PPARα激动剂后肝脏LPL表达增加, ApoCⅢ的分泌降低, 且呈时间剂量依赖性地降低[18].

3 FXR-酶-TG通路

FXR下调FAS和肝脂酶(hepatic lipase, HL)的表达, 从而降低血浆中的胆固醇和TG含量[19]. FAS和HL是TG代谢中的关键酶, 其表达和活性变化与体内甘油三脂的含量密切相关[20]. FAS主要存在于肝、肾、脑、肺、乳腺及脂肪等组织, 是脂肪酸生物合成过程中将小分子碳单位聚合生成长链脂肪酸的关键酶, 可促进肝脏合成新的脂肪[21]. HL是一种糖蛋白, 由肝细胞合成和分泌, 具有磷脂酶Al和TG水解酶的活性. HL可催化残粒脂蛋白和HDL中甘油三脂和磷脂水解. 大量研究证实[22]HL在HDL代谢中发挥重要作用. 此外, HL还可以作为配体促进肝细胞摄取HDL中的胆固醇或LDL残粒、促进肝细胞摄取含apoB类脂蛋白[23,24]. 脂肪酸的合成在细胞质中进行, 合成反应过程中有数种酶参与, 其中FAS是最重要的酶. 正常情况下, FAS将乙酞CoA中的二碳合成脂肪酸, 再与甘油形成甘油三脂, 可促进肝脏合成新的脂肪. 此外, FAS是SREBP-lc所调控的下游基因. 抑制FAS及HL的活性, 最终使血浆中甘油三脂含量减少[22,25].

4 FXR-LPL-TG通络

FXR可通过调节LPL从而降解脂蛋白中的甘油三脂和磷[26]. FXR对LPL的调节依赖于LPL的2个辅活化因子: (Apo)CⅡ和(Apo)CⅢ. (Apo)是LPL的激活因子, (Apo)CⅢ是LPL的抑制因子[27-29]. FXR激活后活化(Apo)CⅡ, 同时降低(Apo)CⅢ的表达, 最终的叠加效应是进一步激活LPL, 增加VLDL和CM中的TG的水解[30].

5 FXR-PLTP-TG通路

FXR可上调磷脂转运蛋白(phos pholipid transferprotein, PLTP)转录, 最终降低血浆TG. PLTP是一种分泌蛋白, 最初发现于线粒体和微粒体膜内,主要存在于肝脏和小肠[31]. PLTP具有促进肝脏可溶性物质交换和运输的作用, 其后发现他对磷脂有较强的结合能力[31]. PTLP被FXR激活后可介导磷脂和胆固醇从富含甘油三脂的脂蛋白向HDL转运, 维持血浆中, HDL的水平, 促进血浆中脂质的降低[32]. PLTP在小鼠体内的过表达, 可加速肝脏对HDL中脂质的摄取和清除. 此外, PLTP在胞内则促进胆固醇的转化如生成胆汁酸、胆固醇酯、类固醇激素等[33].

6 FXR-VLDL-TG通路

FXR可诱导VLDL受体的表达, 增加肝脏及外周组织对胆固醇的吸收利用[34]. FXR激活后可降低游离脂肪酸FFA的合成和降低从肝脏分泌VLDL[9]. Schmedt和Dallinga-Thie等[35,36]的研究显示, VLDL受体基因缺陷小鼠的脂蛋白、血清总胆固醇、TG和游离脂肪酸水平与野生小鼠没有差别, 而当VLDLR转基因小鼠和VLDLR缺陷小鼠分别给予高脂饮食后, 转基因小鼠血清TG水平明显降低, 而缺陷小鼠甘油三脂水平明显升高. 当缺乏VLDLR时, VLDL不受影响, 但是循环血液中的TG明显升高.

7 FXR-SDC1-TG通路

FXR可诱导Syndecan1(SDC1)的转录, 降低血浆TG水平. SDC1是跨膜的硫酸乙酰肝素蛋白聚糖(heparin sulfate proteoglycan, HSPGs)的家族成员之一, 生理状态下主要表达于上皮细胞表面[37]; SDC1通过脂蛋白脂肪酶、apoE、肝脂酶等桥蛋白与脂蛋白相连, 在肝脏清除脂蛋白残粒中发挥作用[11].

糖尿病是全世界高发病率、高死亡率的疾病之一[38-41], 肝脏在葡萄糖糖代谢平衡中起着至关重要的作用, 是糖异生和糖原合成的重要器官. FXR的激活显示了对糖尿病以及胆汁酸代谢异常所致疾病和其他代谢疾病的治疗作用[42-44]. 有实验研究显示[45], FXR在禁食后的小鼠体内表达增加, 相应的受FXR调节的代谢基因如过氧化物酶体增殖物激活受体(PPARγ)、PPARγ共活剂-1a(PGC-1a), 肝细胞核因子(HNF-4α)等显著升高, 而HL的合成明显减少. 由此可见, FXR在糖脂代谢的调控中发挥重要作用. 小鼠肝细胞体内外的实验研究显示, PGC-1α、环磷酸腺苷的超表达能增加FXR的表达和活性. FXR通过激活SHP的活性, 通过SHP下调LRH-1, 最终抑制胆固醇7α-羟化酶活性, 胆汁酸的合成受到抑制, 因胆汁酸可抑制PGC-1α的活性, 因此FXR抑制BAs合成的同时间接激活了PGC-1α的活性, 而PGC-1α、CAMP均为体内代谢的启动和调节因子.

8 结论

由此可见, FXR对TG的调控机制涉及多基因、多靶点、多途径共同作用, 最终维持内外环境TG及相关脂质的动态平衡. 除此之外, FXR作为一种多靶点的核受体, 具有多种调节作用, 涉及脂肪、糖、胆汁酸及胆固醇等多种代谢相关的基因和信号转导的途径, 其表达异常与糖尿病、脂肪肝、胆结石(gallstone disease, GD)等疾病密切相关. 大量的实验研究显示[44-46], 激活的FXR对糖尿病、脂肪肝等多种代谢疾病有良好的治疗作用. 然而, FXR在其他组织, 例如脂肪组织、骨骼肌、胰腺和中枢神经系统的作用仍需进一步的深入研究. FXR作为全身能量代谢的一个调节器, 有望成为多种代谢疾病的一个治疗靶点.

评论

背景资料

高甘油三脂血症作为代谢综合征(MS)的组分, 是非酒精性脂肪性肝病(NAFLD)和心血管疾病的独立危险因素之一.

同行评议者

周南进, 研究员, 江西省医学科学研究所

研发前沿

目前对甘油三酯代谢的研究涉及相关酶、脂蛋白和受体等多种途径, 但其机制尚未完全阐明.

相关报道

经研究证实, FXR在调控TG代谢中发挥重要作用. Sinal等给予FXR基因敲除小鼠高脂饮食后发现TG含量明显高于对照组, 给予FXR激动剂后TG含量较对照组明显降低.

创新盘点

FXR作为一种多靶点的核受体, 具有多种调节作用, 涉及脂肪、糖、胆汁酸及胆固醇等多种代谢相关的基因和信号转导途径, 其表达异常与糖尿病、脂肪肝、胆结石等疾病密切相关.

同行评价

法尼醇X受体( FXR)广泛参与糖脂及胆汁酸等代谢, 逐渐成为相关代谢疾病研究的热点, 有关FXR调控脂代谢特别是甘油三酯代谢通路的研究, 对阐明NAFLD及MS的发病机制、寻找有效的治疗靶点具有重要的意义.

备注

编辑:翟欢欢 电编:鲁亚静

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