需重新审视:高密度脂蛋白胆固醇-“好”胆固醇?
高密度脂蛋白胆固醇:“好”胆固醇?
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1975年,Miller和Miller[1]报道低浓度高密度脂蛋白胆固醇(high density lipoprotein-cholesterol,HDL-C)和心血管疾病风险增加相关。此后,Frammingham大规模人群观察性研究显示,HDL-C浓度和冠心病发病率负相关[2],HDL-C被普遍视为“好”胆固醇。然而,多项设计严谨的大规模临床研究,包括AIM-HIGH、dal-OUTCOMES、HPS2-THRIVE等结果提示高剂量烟酸、胆固醇酯转移蛋白(cholesteryl ester transfer protein,CETP)抑制剂可有效升高HDL-C浓度,却并未降低心血管事件风险[3, 4, 5]。此外,孟德尔随机研究显示,基因组中多种升高HDL-C浓度的基因突变未改善心血管预后[6]。HDL-C和心血管疾病的关系需重新审视。
1项流行病学研究提示,HDL-C并不能简单等同于“好”胆固醇,过高或过低浓度的HDL-C均与心血管不良事件相关。Zanoni等[7]发现编码HDL-C受体的清道夫受体-BI(scavenger receptor BI,SR-BI)基因(SCARB1)P376L突变携带者HDL-C浓度明显升高,纯合子和杂合子携带者血浆HDL-C浓度分别为110.1 mg/dl和86.9 mg/dl,然而冠心病发生风险却显著增加(OR=1.79,P=0.018),与SR-BI功能缺失导致高密度脂蛋白(high density lipoprotein,HDL)参与的胆固醇逆转运功能受损相关。2项旨在评估极高浓度HDL-C的健康人群全因死亡率的前瞻队列研究显示,极高浓度HDL-C(男性>97 mg/dl,女性>116 mg/dl)的健康人群全因死亡风险增加,HDL-C浓度和全因死亡发生率呈U型关系[8]。基于英国生物银行数据库的研究发现,相较中等浓度组(HDL-C 40~60 mg/dl),极高浓度HDL-C组(>80 mg/dl)全因死亡(HR=1.96,95%CI:1.42~2.71,P<0.001)和心血管死亡风险增加(HR=1.71,95%CI:1.09~2.68,P=0.02)[9]。因此,HDL-C浓度并不是越高越好。浓度不能反映HDL-C颗粒的功能,此外,某些因素可将HDL-C的抗炎症状态转换为致炎症状态。
HDL通过介导胆固醇逆转运,抗炎、抗氧化等机制,发挥着抗动脉粥样硬化等多种心血管保护作用。HDL-C浓度并不能反映其功能状态,HDL和心血管事件风险的相关研究焦点由HDL-C浓度转变为了HDL功能。HDL胆固醇流出能力(cholesterol efflux capacity,CEC)是指HDL介导巨噬细胞胆固醇流出的能力,这是胆固醇逆转运过程的第1步,是HDL主要生物学功能之一,已在动物模型中证实可延缓动脉粥样硬化斑块的进展[10]。2014年新英格兰杂志发表的达拉斯心脏研究显示,HDL-CEC和心血管事件发生风险负相关[11]。一项纳入了18项观察性研究的荟萃分析示,高HDL-CEC人群的冠状动脉疾病风险减低,比值比为0.52(95%CI:0.37~0.71),二者呈线性负相关性[12]。此外,孟德尔随机研究显示,LIPG基因突变促进HDL-CEC过程,升高HDL-C浓度的同时减少了CHD发生风险;LCAT和LIPC基因突变升高HDL-C浓度,但未改善HDL-CEC能力,CHD发生风险增加[6],再次印证了相比于HDL-C浓度,HDL功能更具有心血管疾病预测价值。此外,PREVEND研究发现HDL的抗炎作用和心血管疾病发生率呈负相关性(OR=0.74,95%CI:0.61~0.90,P=0.002),独立于高敏C反应蛋白水平[13]。
HDL具有高度异质性,表现为HDL颗粒密度、大小、电荷、蛋白质及脂质组分存在差异。参与HDL颗粒构成的蛋白质和脂质有200余种,不同蛋白质和脂质“组合”造成HDL结构的差异化,并导致HDL理化特性和功能的异质性[14, 15]。早期HDL分类主要基于HDL的理化性质,如根据颗粒密度,分为HDL2和HDL3,不同亚型HDL和冠心病的相关性研究结论并不一致。近年来,HDL蛋白组学成为新的研究焦点,上百种蛋白质参与着HDL的构成,影响着HDL的生物学功能。除外载脂蛋白(apolipoprotein,Apo)A1和ApoA2,Morton等[16]研究提示含有ApoE的HDL颗粒增大、血浆清除速度增快,提示ApoE-HDL促进胆固醇流出,具有抗动脉粥样硬化作用。在前瞻性队列研究中,该团队发现ApoE-HDL和心血管疾病风险负相关。此外,研究发现包含ApoM的HDL颗粒可以通过抑制内皮细胞表达细胞黏附因子,从而发挥抗炎作用。与此同时,HDL蛋白组学研究显示,HDL也参与着补体通路活化、抗感染、蛋白酶抑制等过程[17]。
基于HDL的心血管保护作用,以改善HDL功能为目标的临床试验广泛开展。PREDIMED研究发现富含橄榄初榨油或坚果的地中海饮食显著改善了HDL功能,包括CEC功能,提供了一种降低心血管风险的生活方式干预方法[18]。血管生长素样蛋白反义寡核苷酸促进HDL胆固醇逆转运过程,在动物模型中被证实可以延缓动脉粥样硬化进展,并在2期临床试验中展现了良好的安全性和耐受性,为降低动脉粥样硬化残余风险带来希望[19, 20, 21]。此外,重组HDL或HDL类似物相关研究均未获得阳性结果。CARAT研究显示重组HDL CER-001未改善急性冠脉综合征患者动脉粥样硬化斑块体积[22]。Milano Pilot研究显示HDL类似物MDCO-216促进胆固醇流出,然而并未改变斑块体积[23]。可能与药物剂量或使用时机不当,以及重组HDL或HDL类似物缺乏抗炎、抗氧化等多种HDL生物学功能有关,但还需更多研究证据。尽管多项关于CETP抑制剂的随机对照研究为阴性结果,但是与第1代CETP抑制剂不同,第2代CETP抑制剂可能具有多靶点的调脂作用,包括降低LDL-C、中间密度脂蛋白胆固醇等[24]。孟德尔随机研究提示,同时具有基因预测到低水平CETP和前蛋白转化酶枯草溶菌素9的患者冠心病风险降低[25, 26]。有趣的是,尽管没有降低心血管风险的确切作用,近期研究发现抑制CETP升高HDL-C的同时改善了脓毒症患者的预后[27]。
围绕HDL的临床研究和药物研发仍在继续,流行病学研究证实HDL-C仍然是评估心血管风险的重要标志物,HDL-C水平和全因死亡率、心血管疾病死亡率呈U型关系,并非越高越好。HDL的异质性为临床研究带来诸多的不确定性和复杂性;另一方面,HDL介导的胆固醇转运,其抗炎、抗氧化等作用又为它在心血管疾病、感染性疾病、肿瘤性疾病等领域应用带来新的希望。如何找到有效改善HDL功能的治疗靶点可能是未来的研究方向。
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