Hafiane Anouar, Ronca Annalisa, Incerti Matteo, Rossi Alessandra, Manfredini Matteo, Favari Elda
Department of Medicine, Faculty of Medicine, Research Institute of the McGill University Health Centre, 1001 Boul Decarie, Montreal, Québec, H3A 1A1, Canada.
Department of Food and Drug, University of Parma, Parco Area Delle Scienze, 27/A, 43124, Parma, Italy.
Eur J Med Res. 2025 Apr 11;30(1):266. doi: 10.1186/s40001-025-02439-0.
Lomitapide reduces plasma low-density lipoprotein cholesterol (LDL-C) and is approved for the treatment of homozygous familial hypercholesterolemia (HoFH). This study aims to determine the effect of lomitapide on HDL and cholesterol efflux in a cohort of patients with HoFH.
Analysis included plasma samples from 17 HoFH patients enrolled in the lomitapide phase 3 Aegerion clinical study (NCT00730236). Samples taken at baseline (pre-lomitapide) and weeks 56 and 66 (assumed steady-state on lomitapide) were analyzed for HDL-C levels and cholesterol efflux capacity (CEC) pathways via ABCA1, ABCG1, and SR-BI cholesterol uptake.
Treatment with lomitapide is associated with a statistically significant decrease of both LDL-C and apo B when compared to baseline levels, p < 0.01. However, the reduction of Lp(a) appears only at a higher dose when compared to baseline (- 27% against values around - 55% for LDL-C and apo B). HDL-C shows a small 4.2% increase between the baseline and the treatment with a high dosage of lomitapide, while apo A-I displays an opposite small 3% decrease. Total efflux and ABCA1 mediated CEC decreased especially at higher dosage of lomitapide, with marked dose-dependent increase of SR-BI cholesterol uptake (+ 21.4% and + 64.3%, respectively, at a low and high dosages of lomitapide). However, ABCG1 did not change consistently.
Our report raises the hypothesis that lomitapide promotes lipidation of HDL particles independently of ABCA1 and ABCG1 through a process involving SR-BI pathway. This effect impairs the total efflux process suggesting that lomitapide drives the reverse cholesterol transport through SR-BI receptors in HoFH patients.
洛美他派可降低血浆低密度脂蛋白胆固醇（LDL-C），已被批准用于治疗纯合子家族性高胆固醇血症（HoFH）。本研究旨在确定洛美他派对一组HoFH患者高密度脂蛋白（HDL）和胆固醇流出的影响。
分析纳入了洛美他派3期Aegerion临床研究（NCT00730236）中的17例HoFH患者的血浆样本。对基线（洛美他派治疗前）以及第56周和第66周（假定处于洛美他派治疗的稳态）采集的样本进行HDL-C水平分析，并通过ABCA1、ABCG1和SR-BI胆固醇摄取分析胆固醇流出能力（CEC）途径。
与基线水平相比，洛美他派治疗使LDL-C和载脂蛋白B（apo B）均有统计学显著下降，p < 0.01。然而，与基线相比，脂蛋白（a）[Lp(a)]仅在较高剂量时出现降低（LDL-C和apo B降低约55%，而Lp(a)降低27%）。HDL-C在基线和高剂量洛美他派治疗之间有4.2%的小幅升高，而载脂蛋白A-I（apo A-I）则有3%的小幅相反降低。总流出量和ABCA1介导的CEC在洛美他派较高剂量时尤其降低，SR-BI胆固醇摄取有明显的剂量依赖性增加（洛美他派低剂量和高剂量时分别增加21.4%和64.3%）。然而，ABCG1没有持续变化。
我们的报告提出了一个假设，即洛美他派通过涉及SR-BI途径的过程，独立于ABCA1和ABCG1促进HDL颗粒的脂化。这种作用损害了总流出过程，表明洛美他派通过SR-BI受体驱动HoFH患者的胆固醇逆向转运。
