Wen Yi, Li Hongxia, Smith Sydney, Lin Yanzhu, Chen Yan Q, Bellinger Melissa, Zhen Eugene Y, Beyer Thomas P, Siegel Robert W, Qian Yuewei, Ruotolo Giacomo, Konrad Robert J
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA (Drs Wen, Li, Smith, Lin, Chen, Bellinger, Zhen, Beyer, Siegel, Qian, Ruotolo, and Konrad).
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA (Drs Wen, Li, Smith, Lin, Chen, Bellinger, Zhen, Beyer, Siegel, Qian, Ruotolo, and Konrad).
J Clin Lipidol. 2025 Jul-Aug;19(4):1073-1084. doi: 10.1016/j.jacl.2025.06.008. Epub 2025 Jun 15.
Cholesteryl ester transfer protein (CETP) mediates the exchange of triglycerides (TG) from apolipoprotein B (ApoB)-containing lipoproteins to high-density lipoproteins (HDL) and the reciprocal exchange of cholesterol (C) from HDL to ApoB-containing lipoproteins. CETP inhibition increases HDL-C and decreases low-density lipoprotein cholesterol (LDL-C) while modestly decreasing TG. Considering that CETP inhibitors block removal of TG from TG-rich lipoproteins (TRL), it is interesting that CETP inhibition decreases TG concentrations. TG levels are largely regulated by lipoprotein lipase (LPL), the enzyme primarily responsible for hydrolyzing TG. The angiopoietin-like 3/8 complex (ANGPTL3/8) is the most potent circulating LPL inhibitor, while the TG-lowering apolipoprotein A5 (ApoA5) acts by suppressing ANGPTL3/8-mediated LPL inhibition.
To better understand CETP biology, we studied the effects of CETP overexpression and CETP inhibition on the levels of ANGPTL3/8 and ApoA5 in circulation using dedicated immunoassays.
CETP-overexpressing transgenic mice had increased TG and normal ANGPTL3/8 levels but manifested dramatically reduced ApoA5 concentrations. Administration of the CETP inhibitor evacetrapib had no effect on ANGPTL3/8 levels in CETP-overexpressing mice or in humans. However, evacetrapib administration increased ApoA5 concentrations in both species. In human subjects, evacetrapib treatment increased circulating ApoA5 levels in the late-stage ACCELERATE and ACCENTUATE studies by 160.1% and 204.7%, respectively.
Our results uncover a previously unrecognized link between CETP and ApoA5 by showing that CETP overexpression reduces ApoA5 levels while CETP inhibition increases ApoA5 concentrations.
胆固醇酯转运蛋白（CETP）介导甘油三酯（TG）从含载脂蛋白B（ApoB）的脂蛋白向高密度脂蛋白（HDL）的交换，以及胆固醇（C）从HDL向含ApoB脂蛋白的反向交换。抑制CETP可升高HDL-C并降低低密度脂蛋白胆固醇（LDL-C），同时适度降低TG。鉴于CETP抑制剂可阻止富含TG的脂蛋白（TRL）中TG的清除，CETP抑制却能降低TG浓度这一点很有意思。TG水平主要由脂蛋白脂肪酶（LPL）调节，LPL是主要负责水解TG的酶。血管生成素样3/8复合物（ANGPTL3/8）是最有效的循环LPL抑制剂，而降TG的载脂蛋白A5（ApoA5）通过抑制ANGPTL3/8介导的LPL抑制发挥作用。
为了更好地理解CETP的生物学特性，我们使用专用免疫测定法研究了CETP过表达和抑制CETP对循环中ANGPTL3/8和ApoA5水平的影响。
过表达CETP的转基因小鼠TG升高，ANGPTL3/8水平正常，但ApoA5浓度显著降低。给予CETP抑制剂依折麦布对过表达CETP的小鼠或人类的ANGPTL3/8水平均无影响。然而，给予依折麦布可使两个物种的ApoA5浓度均升高。在人类受试者中，依折麦布治疗在晚期ACCELERATE和ACCENTUATE研究中分别使循环ApoA5水平升高了160.1%和204.7%。
我们的结果揭示了CETP与ApoA5之间此前未被认识到的联系，表明CETP过表达会降低ApoA5水平，而抑制CETP则会升高ApoA5浓度。
