Division of Vascular Medicine, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Auenbruggerplatz 15 Graz, Austria.
Lilly Research Laboratories, Eli Lilly and Company, 893 Delaware St, Indianapolis, IN 46225, USA.
Eur Heart J. 2023 Jul 1;44(25):2335-2345. doi: 10.1093/eurheartj/ehad261.
Apolipoprotein C-II (ApoC-II) is thought to activate lipoprotein lipase (LPL) and is therefore a possible target for treating hypertriglyceridemia. Its relationship with cardiovascular risk has not been investigated in large-scale epidemiologic studies, particularly allowing for apolipoprotein C-III (ApoC-III), an LPL antagonist. Furthermore, the exact mechanism of ApoC-II-mediated LPL activation is unclear.
ApoC-II was measured in 3141 LURIC participants of which 590 died from cardiovascular diseases during a median (inter-quartile range) follow-up of 9.9 (8.7-10.7) years. Apolipoprotein C-II-mediated activation of the glycosylphosphatidylinositol high-density lipoprotein binding protein 1 (GPIHBP1)-LPL complex was studied using enzymatic activity assays with fluorometric lipase and very low-density lipoprotein (VLDL) substrates. The mean ApoC-II concentration was 4.5 (2.4) mg/dL. The relationship of ApoC-II quintiles with cardiovascular mortality exhibited a trend toward an inverse J-shape, with the highest risk in the first (lowest) quintile and lowest risk in the middle quintile. Compared with the first quintile, all other quintiles were associated with decreased cardiovascular mortality after multivariate adjustments including ApoC-III as a covariate (all P < 0.05). In experiments using fluorometric substrate-based lipase assays, there was a bell-shaped relationship for the effect of ApoC-II on GPIHBP1-LPL activity when exogenous ApoC-II was added. In ApoC-II-containing VLDL substrate-based lipase assays, GPIHBP1-LPL enzymatic activity was almost completely blocked by a neutralizing anti-ApoC-II antibody.
The present epidemiologic data suggest that increasing low circulating ApoC-II levels may reduce cardiovascular risk. This conclusion is supported by the observation that optimal ApoC-II concentrations are required for maximal GPIHBP1-LPL enzymatic activity.
载脂蛋白 C-II（ApoC-II）被认为可以激活脂蛋白脂肪酶（LPL），因此可能是治疗高甘油三酯血症的一个靶点。但其与心血管风险的关系尚未在大规模的流行病学研究中得到证实，特别是在载脂蛋白 C-III（ApoC-III）作为 LPL 拮抗剂的情况下。此外，ApoC-II 介导的 LPL 激活的确切机制尚不清楚。
在 LURIC 研究的 3141 名参与者中测量了 ApoC-II 的浓度，其中 590 人在中位（四分位间距）9.9（8.7-10.7）年的随访期间死于心血管疾病。使用荧光脂酶和极低密度脂蛋白（VLDL）底物的酶活性测定研究了 ApoC-II 对糖基磷脂酰肌醇高密度脂蛋白结合蛋白 1（GPIHBP1）-LPL 复合物的介导激活作用。ApoC-II 的平均浓度为 4.5（2.4）mg/dL。ApoC-II 五分位组与心血管死亡率的关系呈反向 J 型趋势，风险最高的是第一（最低）五分位组，风险最低的是中间五分位组。与第一五分位组相比，在包括 ApoC-III 作为协变量的多变量调整后，所有其他五分位组与心血管死亡率降低相关（均 P < 0.05）。在使用基于荧光底物的脂肪酶测定的实验中，当添加外源性 ApoC-II 时，ApoC-II 对 GPIHBP1-LPL 活性的影响呈钟形关系。在含有 ApoC-II 的 VLDL 底物的脂肪酶测定中，GPIHBP1-LPL 酶活性几乎完全被中和性抗 ApoC-II 抗体阻断。
目前的流行病学数据表明，循环中低水平的 ApoC-II 水平升高可能降低心血管风险。这一结论得到了以下观察结果的支持，即最佳的 ApoC-II 浓度对于最大的 GPIHBP1-LPL 酶活性是必需的。
