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胆固醇代谢异常与糖尿病视网膜病变的关系探究

Study on the relationship between abnormal cholesterol metabolism and diabetic retinopathy

来源期刊： 眼科学报 | 2023年9月 第38卷 第9期： 617-623 发布时间： 收稿时间：2024/1/18 8:33:29 阅读量：3773
作者：
毛一恒,
冯洁,
何润田,
关键词：
糖尿病视网膜病变胆固醇逆向转运途径胆固醇转运障碍高脂血症糖尿病微血管并发症
diabetic retinopathy cholesterol reverse transport pathway cholesterol transport disorder hyperlipidemia diabetic microvascular complication
DOI：
10.12419/2303080001
收稿时间：
 
修订日期：
 
接收日期：
 
糖尿病视网膜病变是最为常见的糖尿病微血管并发症，主要由糖尿病引起的机体代谢紊乱导致。而然在临床工作中发现，部分患者通过单纯控制血糖以延缓糖尿病视网膜病变进展，所取得效果不甚理想，一些其他因素对于糖尿病视网膜病变的发生、发展，也起到不可忽视的作用。研究表明，在并发高脂血症的糖尿病视网膜病变患者中，胆固醇代谢异常是诱发视网膜病变的主要原因之一。胆固醇代谢异常通过减弱肝脏X受体，导致胆固醇在视网膜上不断积累，降低视网膜血管内皮功能，从而造成视网膜缺血、缺氧环境的形成，又可通过增加炎症因子和细胞黏附分子-1的表达，使原本病态的糖尿病视网膜血管变得更加脆弱，该文总结了糖尿病视网膜病变的病理因素，对比分析当前糖尿病视网膜病变的主要治疗手段，通过分析胆固醇逆向转运(cholesterol reverse transport,RCT)途径转运对糖尿病视网膜病变发生、发展的影响，发现降低高血脂可提高糖尿病视网膜病变的治愈率，这将为糖尿病视网膜病变的临床防治工作提供新思路。
Diabetic retinopathy is the most common diabetic microvascular complication, which is mainly caused by metabolic disorders caused by diabetes. However, in clinical work, it is found that some patients do not achieve satisfactory results in delaying the progress of diabetic retinopathy by simply controlling blood sugar, and some other factors contribute to the occurrence and development of diabetic retinopathy. Also played a role that can not be ignored. Studies have shown that abnormal cholesterol metabolism is one of the main causes of retinopathy in diabetic retinopathy patients with hyperlipidemia. Abnormal cholesterol metabolism leads to the accumulation of cholesterol in the retina and the decrease of retinal vascular endothelial function by weakening the X receptor in the liver, resulting in the formation of retinal ischemia and hypoxia environment. it can also increase the expression of inflammatory cytokines and cell adhesion molecule-1 to make the originally morbid retinal vessels more fragile. This paper summarizes the pathological factors of diabetic retinopathy. By comparing and analyzing the main treatment methods of diabetic retinopathy at present, and by analyzing the influence of cholesterol reverse transport (cholesterolreversetransport,RCT) pathway on the occurrence and development of diabetic retinopathy, it is found that reducing hyperlipidemia can improve the cure rate of diabetic retinopathy, which will provide new ideas for the clinical prevention and treatment of diabetic retinopathy.
糖尿病视网膜病变(diabetic retinopathy,DR)是糖尿病最常见、最严重的微血管并发症。DR在中国大陆的总体患病率估计为34.6%，范围为11.9%～43.1%。DR仍然是发达国家和发展中国家工作年龄人口失明的主要原因[1]。我国居民DR知晓率仅为50%左右，病变防治观念较弱，致使DR的早期发现尤为困难[2]。当DR发展到视力严重受损时，可用治疗方案受到限制。晚期DR需要反复通过激光光凝或玻璃体腔注射抗血管内皮生长因子(vascular endothelial growth factor, VEGF)治疗，严重降低患者生活质量和增加经济负担。DR的诊治一直是眼科工作的重点，然而其发病机制十分复杂，全身多种代谢途径都会对疾病的发展产生重大的影响，单纯控制血糖和血压不能完全抑制DR的进展[3]。大量研究表明，脂代谢异常是催动DR发生、发展的又一重要影响因素[4]。同时，我国高胆固醇血症合并DR患者数量日益增加，相对于单纯糖尿病引起的视网膜病变，脂代谢紊乱造成的视网膜病变使得DR的发生机制更加复杂，对于治疗效果更加充满不确定性。了解高胆固醇血症对眼底视网膜的影响，对降低DR致盲率有一定意义。

1 DR发生机制

DR是以糖尿病为基础所导致的微血管病变，可将其分为非增殖性DR(non-proliferative diabetes retinopathy,NPDR)和增殖性DR(proliferative diabetes retinopathy,PDR)，糖尿病眼底病变的特征是由于血液-视网膜屏障(blood retinal barrier,BRB)破裂引发黄斑内和视网膜下积聚液体而导致黄斑肿胀或增厚临床主要表现为视网膜出血、新生血管、微动脉瘤，严重者可导致糖尿病性黄斑水肿(diabetic macular edema,DME)、视网膜脱离[5]。PDR的病理机制受多种因素的共同调控。研究表明，其主要与机体VEGF、血管细胞间黏附分子-1(intercellular cell adhesion molecule-1,ICAM-1)及PI3K-AKT-mTOR信号通路、TGF-β/Smad信号通路、微RNA(microRNA,miRNA)等信号调控通路的上下游表达水平相关[6]。内皮功能障碍是DR发病的核心机制。

1.1 DR的治疗

目前DR的治疗策略主要是控制微血管并发症，包括玻璃体内药物注射、激光光凝和玻璃体手术。玻璃体内注射抗VEGF药物是早期和晚期DR的主要治疗方法，相较于传统的激光治疗只能稳定视力，抗VEGF治疗既可以改善视力，又可以减少眼部不良反应。局灶性/网格性黄斑激光治疗已被证明可以有效缓解DME，并可将中度视力丧失的风险降低50%。全视网膜光凝(panretinal laser photocoagulation,PRP)也被用于治疗PDR[7]，并降低在玻璃体积血等高危并发症的情况下所出现的严重视力丧失风险。激光治疗通过直接闭合漏出的微动脉瘤、减少视网膜血流量、改善视网膜组织的氧合状态等途径治疗糖尿病。但激光治疗可能对视网膜细胞造成永久性损伤，导致轻度中枢视力丧失和夜间视力下降。虽然抗VEGF治疗日益成为DR治疗的主要手段，但激光治疗在辅助治疗或抢救治疗中，仍然发挥着重要的作用。

2 胆固醇代谢途径在DR中发挥的作用

在糖尿病中，营养供应和利用之间的平衡被打破，导致血糖水平上升，并伴有以血浆甘油三酯和低密度胆固醇水平升高，以及高密度脂蛋白胆固醇水平降低为特征的血脂异常[8]。组织无法高效利用营养物质而导致大量营养物质堆积、促进炎症和凋亡发生，从而导致血管损伤。胆固醇主要经由肝脏代谢，是血浆脂蛋白和细胞膜合成的必要成分，代谢主要包括三种途径：转化为胆汁酸、转化为甾体激素和转化为维生素D3。正常情况下，胆固醇在视网膜的输入包括局部生物合成和从视网膜色素上皮(retinal pigment epithelium,RPE)细胞基底膜上的循环摄取脂蛋白颗粒。视网膜通过严格控制胆固醇的输入与输出的比值出来维持其胆固醇稳态，并通过胆固醇逆向转运(reverse cholesterol transport,RCT)途径将多余胆固醇排出体外，RCT途径受肝脏X受体(liver X receptor,LXR)激活及其下游调节因子三磷酸腺苷( a d e n o s i n e triphosphate,ATP)结合核亚家族A成员1(ATP-binding cassette sub-family A member 1,ABCA1)和ATP结合核亚家族G成员1 (ATP-binding cassette sub-family G member 1,ABCG1)调控[9]。并通过降低内皮细胞的氧化应激而对视网膜起保护作用，ABCA1和ABCG1在大多数组织细胞中广泛表达，它们在胆固醇向细胞外载脂蛋白A1(apolipoprotein A1,ApoA1)的转移中发挥关键作用[10]。生理条件下，LXR的转录活性随着细胞胆固醇水平的升高而增加。但DR在高葡萄糖环境会减弱LXR的激活，并使得细胞膜上转运蛋白ABCA1和ABCG1的下调，进而导致视网膜上胆固醇水平明显高于正常水平[11]。在此种机制作用下糖尿病患者本就脆弱的视网膜血管将更加容易发生病变。

2.1 RCT途径中SIRT1-LXR轴在DR发生、发展中的作用

LXR包括两个亚型：LXRα和LXRβ，糖尿病会导致视网膜细胞中LXRα、LXRβ和沉默信息调节因子蛋白1(Sirtuin 1,SIRT1)水平显著下降[12]。LXR的激活具有使RCT正常化、预防糖尿病引起的炎症、减少促炎巨噬细胞的数量、防止DR样病变等作用。视网膜中的胆固醇代谢主要有2条途径：1)高密度脂蛋白胆固醇介导的RCT；2)通过细胞色素P450酶将胆固醇代谢为更易分解的氧甾醇[13]。除了在胆固醇代谢中的既定作用，LXR还具有抑制炎症基因的表达从而控制免疫和炎症的作用。此外，LXR可减少循环染色体异常细胞(cyclic chromosome abnormal cells,CAC)的数量并增强巨噬细胞的激活，CAC增多具有提示细胞癌变的作用[14]。研究表明LXR基因缺失的小鼠，即使在没有高血糖的情况下，也会出现DR[9]。另一种关键的代谢调节剂SIRT1被证明通过LXR依赖机制发挥其有益作用[15]。SIRT1是酵母SIR2基因在哺乳动物中的同源基因，已被证明在衰老、细胞凋亡、神经保护、促进胰岛素分泌、降低糖耐量和神经发育中发挥作用[15]。SIRT1通过脱乙酰基激活LXR，随后LXR促进ABCA1和ABCG1的表达[16]。高血糖环境导致SIRT1表达水平下调，进而抑制LXR及其配体活化并阻碍ABCA1的激活，影响视网膜细胞内胆固醇的正常转运。
SIRT1-LXR轴在分离自DR患者供体组织或DR动物模型的视网膜细胞中表达下调。2020年，Hammer等[17]利用MCDB131培养基模拟牛视网膜内皮细胞(bovine retinal endothelial cells,BREC)的生长环境，并通过增加或不增加1μg/mL DMHCA(一种选择性LXR激动剂)来代替非禁食或禁食后细胞内SIRT1-LXR轴的转运情况。研究表明，与高胆固醇组相比，禁食组(不加DMHCA)SIRT1表达水平升高8倍，且LXR表达水平升高。SIRT1的直接激活致糖尿病视网膜炎症发生率降低至1/3，进而改善糖尿病引起的视觉功能损害。由此可见，糖尿病导致的SIRT1信号减少引起胆固醇代谢紊乱，并通过下调LXR信号增加促炎细胞因子的表达。
高胆固醇也可直接作用于视网膜ABCA1和ABCG1受体。ABCA1更集中地定位于RPE的顶端侧，而ABCG1定位于基底侧。ABCA1或ABCG1在人类视网膜中比在肝脏中多1.4倍或2.5倍，此外，位于视网膜上皮细胞两侧的ABCA1在体外受LXR调节[18]。ABCA1在RCT过程中与载脂蛋白结合，参与高密度脂蛋白胆固醇的形成。ABCA1促进胆固醇和鞘磷脂的重新分布，并帮助胆固醇自由流动到载脂蛋白，后者被酯化为成熟的高密度脂蛋白胆固醇颗粒，ABCG1是一种半转运体，主要将细胞内胆固醇转移到细胞外成熟的高密度脂蛋白胆固醇，从而降低细胞内胆固醇浓度，防止内皮细胞中脂质堆积[18]。RCT的第一步，胆固醇从外周组织逆向转运至肝脏，是由ATP结合盒转运体ABCA1和ABCG1介导的，视网膜清道夫受体I类、CD36和小窝蛋白-1同时参与。研究证明，IL-1β、IL-6和VEGF是导致DR患者视网膜新生血管形成的关键影响因素，而ABCA1的激活能抑制IL-1β的表达，在视网膜缺血、缺氧的环境下，对视网膜神经节细胞具有保护作用[19]。当ABCA1转运发生障碍时可导致细胞内胆固醇聚集形成泡沫细胞促进血管硬化。大量研究显示，DR中ABCA1和ABCG1含量明显下降，在玻璃体内注射LXR激动剂TO901317可以上调ABCA1表达从而抑制视网膜炎症反应[20-21]，但具体抑制机制还有待研究，这可能会成为DR治疗药物新的研究方向。

2.2 RCT途径促进VEGF高表达产生病理性新生血管

RCT途径中高密度脂蛋白胆固醇具有明显促进血管内皮细胞分泌VEGF的作用。高密度脂蛋白胆固醇颗粒中的人磷脂酰乙醇(phosphatidylethanol,PEth)通过和人高密度脂蛋白受体-I(human high-density lipoprotein receptor-I,CLA-1)结合促进VEGF的分泌增加。高密度脂蛋白胆固醇颗粒与PEth结合能力与其数量不呈正相关，而是可能与高密度脂蛋白胆固醇颗粒的形状有关，高密度脂蛋白胆固醇颗粒呈球状，靠近CLA-1受体结合部位的磷脂可能影响CLA-1的功能，而与高密度脂蛋白胆固醇颗粒相对的磷脂可能不影响CLA-1受体的功能，所以即使是少量(占总磷脂的0.1%~0.5%)的PEth也能促进培养的人内皮细胞分泌VEGF[22]。
内皮祖细胞(endothelial progenitor cells,EPC)来源于骨髓，具有维持血管内皮完整性、修复损伤的血管和促进血管再生的作用，是负责维持和修复血管系统的关键细胞。但EPC在高血糖或高胆固醇环境中表现为功能紊乱，DR时血管内皮生长因子诱导的新生血管可能是由于血管EPC的循环和募集增加所致[23]。
VEGF是一种细胞因子糖蛋白(通常以二聚体分子的形式存在)，负责生理状态下或病理状态下的血管生成[24]。VEGF的过表达可诱导视网膜内皮细胞的增殖和通透性的增加从而产生病理性新生血管[25]。
1型糖尿病(type 1 diabetes,T1DM)和2型糖尿病(type 2 diabetes,T2DM)都与高脂血症状态有关，由于T2DM的胰岛素抵抗和T1DM缺乏外源性胰岛素的产生，尽管患者血糖水平很高，但细胞对葡萄糖的吸收非常少[26]。这种糖代谢相对不足的状态会促进脂肪分解和胆固醇积累，最终导致血脂升高，而高脂血症又反过来促进DR和DME的发展。并发高脂血症的DR患者因其脂质颗粒在视网膜的内皮细胞上积聚会导致血管损伤和局部血流受损，更加重了视网膜缺氧微环境[27]。缺氧引起视网膜内皮细胞功能异常和VEGF表达增加，脂质堆积又造成的血管损伤导致BRB的破坏。同时缺氧还通过缺氧诱导因子-1α(hypoxia inducible factor-1,HIF-1α)促进VEGF高表达[28]。HIF-1α是参与缺氧反应和修复细胞内氧生态位的核心调节因子，HIF-1α水平的持续升高增加机体糖酵解反应和促进红细胞生成，进而削弱了线粒体代谢并导致血液变稠[29]。Rigiracciolo等[30]证实，在缺氧条件下，HIF-1α调节VEGF基因的转录激活，并以时间依赖方式增强血管生成。

2.3 高脂血症诱发炎症反应激活VEGF对视网膜内皮细胞的损害

RCT途径障碍引起炎症反应在DR的形成中同样起到重要作用，高脂血症加速高血糖导致的线粒体损伤，高脂血症还被证明会导致细胞内钙离子和促炎细胞因子的产生增加。高脂血症增加诱导型一氧化氮合酶( inducible nitric oxide synthase,iNOS)的表达，在炎症过程中一氧化氮(nitric oxide,NO)由L-精氨酸在一氧化氮合酶(nitric oxide synthase,NOS)作用下在巨噬细胞和粒细胞内合成[31]，缺氧和NO能使用重叠的信号通路来稳定HIF表达，并诱发HIF一系列反应[32]。神经细胞来源的NOS和内皮型一氧化氮合酶(endothelial nitric oxide synthase,eNOS)是结构性表达的酶，它们的活动受到细胞内钙离子增加的刺激。钙调神经磷酸酶(calcineurin,CaN)/活化T细胞核因子(nuclear factor of activated T cells,NFAT)通路也参与VEGF调节EPC的生成，同时伴有大量的NO产生[29]。CaN是一种蛋白磷酸酶，由钙结合蛋白分子钙调蛋白激活。在VEGF过度表达的同时，VEGF受体调节的IP3-DAG途径也被过度激活，同时释放大量Ca2+并与钙调蛋白结合激活CaN，这进一步使NFAT去磷酸化促使eNOS蛋白质的表达。在此过程中产生的NO被用于NO-cGMP途径，而NO-cGMP途径是EPC表达所必需的。因此，VEGF通过CaN/NFAT途径诱导EPC表达改变，过量产生NO会增加血液流量和血脑屏障的通透性[33]。
虽然糖尿病患者的视网膜血管生成普遍下降，但疾病缓慢而渐进的特点使修复性(病理性)血管生成得以发生，循环EPC(circulating endothelial progenitor cells,CPC)能够保护血管内皮的完整性和促进缺血组织的再血管化从而防止新生血管的生成。PDR患者视网膜中CPC的数量和功能明显下降，EPC的数量却上升[34]，这些新血管的唤醒从视网膜表面开始，通过Bruch膜向视网膜色素上皮层延伸，多见于玻璃体腔后极部，新形成的血管非常不成熟和脆弱[35]，因此，在炎症反应过程中新生血管很容易受到视网膜早已存在的高渗条件损伤，这些受损的血管将其血管内容物泄漏到视网膜细胞中，并最终进入玻璃体液体中，从而导致玻璃体积血和多种并发症的发生[36]。玻璃体内注射抗VEGF是目前临床上治疗DR的主要手段之一，其通过降低被诱导的VEGF的过度表达，进而减少了PDR中的新生血管和DME中血-视网膜屏障的分解。

2.4 高血脂促进细胞黏附分子-1表达对视网膜的破坏

人体血浆中甘油三酯和游离脂肪酸中含有大量的亚油酸(30%)和花生四烯酸(8%)，而糖尿病患者的总游离脂肪酸水平在600 μmoL或更高，远高于正常人[37]。亚油酸和花生四烯酸都是炎症介质的前体，脂肪酸可能是高血脂促进视网膜炎症过程中的一个重要组成部分[38]。在肝脏，胰岛素刺激脂肪酸转化为甘油三酯，然后分泌为极低密度脂蛋白胆固醇，T2DM的胰岛素抵抗和T1DM的门脉胰岛素水平低将对血浆脂肪酸水平和组成产生深远的影响，T2DM的特征是血液中胆固醇水平升高，以及酯化和非酯化脂肪酸的存在，T1DM导致游离脂肪酸谱改变，ω-6多不饱和脂肪酸与ω-3多不饱和脂肪酸比率增加，在血液中发现的脂肪酸会影响人视网膜微血管内皮细胞(human retinal microvascular endothelial cells,hRVE)中ICAM的表达[37]。ω-6多不饱和脂肪酸亚油酸(18：2ω-6)会增加ICAM-1的表达。ICAM-1是一种95 kD细胞表面糖蛋白，是黏附分子免疫球蛋白超家族的成员，ICAM-1基因位于染色体19p13上，是糖尿病的易感基因，ICAM-1基因rs5498单核苷酸多态和k469e基因与糖尿病的发生具有明显相关性[39-40]。研究显示，DR患者血管表面ICAM-1数量是正常人的数倍。ICAM-1在介导循环系统中白细胞与血管壁的黏附和内皮细胞向血管内膜的迁移方面具有关键作用[41]，DR中ICAM-1表达增加，促进白细胞与ICAM-1和其他黏附分子的黏附过程[42]，从而激活白细胞停滞介导的血-视网膜屏障破坏、毛细血管阻塞和内皮细胞损伤，这是糖尿病发生的一个关键步骤[43]。
目前，有研究表明，通过口服贝特类药物来调节血脂异常和阻止糖尿病视网膜微血管炎症进一步发展，已经取得了良好的临床疗效[44]。贝特类药物能够降低血清甘油三酯含量和升高高密度脂蛋白胆固醇，并且能够抑制趋化因子或黏附分子ICAM-1和降低重组人血管细胞黏附分子(vascular cell adhesion molecule-1,VCAM-1)水平来防止视网膜微血管炎症的发生[45]。这为DR治疗提供了新思路。

3 结语

综上所述，目前大量研究表明RCT途径在胆固醇代谢过程中发挥着重要作用。然而DR发生、发展的机制十分复杂，在基本明确的糖代谢异常所引起的病变基础上，RCT机制障碍所导致的视网膜高脂状态又成为其炎症、微血管病变等病理改变中不可忽视的因素。虽然胆固醇在视网膜上皮细胞和神经细胞中的具体代谢过程还不明确，但RCT途径中的SIRT1-LXR轴激活和如何有效降低高血脂对VEGF表达影响将会是未来治疗DR合并高脂血症的重点。

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发布于: 2022-12-01
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