Leander Karin, Chen Yan Q, Vikström Max, Silveira Angela, Fisher Rachel M, Konrad Robert J, van 't Hooft Ferdinand M
Institute of Environmental Medicine, Unit of Cardiovascular and Nutritional Epidemiology (K.L., M.V.), Karolinska Institutet, Stockholm, Sweden.
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (Y.Q.C., R.J.K.).
Arterioscler Thromb Vasc Biol. 2025 Mar;45(3):443-451. doi: 10.1161/ATVBAHA.124.321308. Epub 2025 Jan 30.
Binding of ANGPTL (angiopoietin-like protein)-3 to ANGPTL8 generates a protein complex (ANGPTL3/8) that strongly inhibits LPL (lipoprotein lipase) activity, as compared with ANGPTL3 alone, suggesting that ANGPTL3/8 concentrations are critical for the regulation of circulation lipoprotein concentrations and subsequent increased coronary heart disease (CHD) risk. To test this hypothesis in humans, we evaluated the associations of circulating free ANGPTL3 and ANGPTL3/8 complex concentrations with lipoprotein concentrations and CHD risk in 2 prospective cohort studies.
Fasting blood samples were obtained in conjunction with the baseline evaluation of 9479 subjects from 2 population-based Swedish cohorts of middle-aged men and women. Standard biochemical blood analyses, including all lipid/lipoprotein measurements, were performed in these samples at baseline. Additional serum samples were stored at -80 °C and used at a later stage for ANGPTL3 and ANGPTL3/8 concentration measurements. Information about incident CHD was obtained for both cohorts by matching to the Swedish National Patient Register and the Cause of Death Register.
ANGPTL3 concentrations showed modest, positive associations with all lipoprotein concentrations but were not associated with CHD risk. In contrast, ANGPTL3/8 concentrations were associated in both cohorts with an atherogenic lipoprotein profile (characterized by increased triglyceride and LDL [low-density lipoprotein] concentrations and reduced HDL [high-density lipoprotein] concentrations). In the combined cohort, ANGPTL3/8 was associated with increased CHD risk. Hazard ratio per 1 SD increase was 1.10 (95% CI, 1.03-1.17) after adjustment for age, sex, cohort, smoking, and hypertension.
Elevated concentrations of ANGPTL3/8, but not ANGPTL3, are associated with an atherogenic lipoprotein profile and increased CHD risk in humans.
血管生成素样蛋白（ANGPTL）-3与ANGPTL8结合形成一种蛋白复合物（ANGPTL3/8），与单独的ANGPTL3相比，该复合物能强烈抑制脂蛋白脂肪酶（LPL）的活性，这表明ANGPTL3/8的浓度对于调节循环脂蛋白浓度以及随后增加的冠心病（CHD）风险至关重要。为了在人类中验证这一假设，我们在两项前瞻性队列研究中评估了循环中游离ANGPTL3和ANGPTL3/8复合物浓度与脂蛋白浓度及CHD风险之间的关联。
在对来自瑞典两个基于人群的中年男性和女性队列的9479名受试者进行基线评估时采集空腹血样。在基线时对这些样本进行标准生化血液分析，包括所有脂质/脂蛋白测量。额外的血清样本保存在-80°C，后期用于测量ANGPTL3和ANGPTL3/8的浓度。通过与瑞典国家患者登记册和死亡原因登记册匹配，获取两个队列中冠心病发病的信息。
ANGPTL3浓度与所有脂蛋白浓度呈适度正相关，但与CHD风险无关。相比之下，ANGPTL3/8浓度在两个队列中均与致动脉粥样硬化脂蛋白谱相关（其特征为甘油三酯和低密度脂蛋白[LDL]浓度升高以及高密度脂蛋白[HDL]浓度降低）。在合并队列中，ANGPTL3/8与CHD风险增加相关。在调整年龄、性别、队列、吸烟和高血压后，每增加1个标准差的风险比为1.10（95%CI，1.03 - 1.17）。
ANGPTL3/8浓度升高而非ANGPTL3浓度升高与人类致动脉粥样硬化脂蛋白谱及CHD风险增加相关。
