Hong Natalie E, Ravodina Anastasia M, Asase Courteney, Gao Huiyun, Cherepanova Olga A, Maiseyeu Andrei
Department of Biomedical Engineering, School of Engineering, Case Western Reserve University, USA; Cardiovascular Research Institute, Case Western Reserve University School of Medicine, USA.
Department of Medicine, School of Medicine, Case Western Reserve University, USA.
Atherosclerosis. 2025 Jul 17;408:120445. doi: 10.1016/j.atherosclerosis.2025.120445.
Itaconate (ITA) is a metabolite produced from the tricarboxylic acid cycle (TCA) that has been shown to regulate atherosclerotic plaque growth and induce stability via immunomodulation. However, lipid metabolism regulation by ITA is currently underexplored in atherosclerosis. Here, we take advantage of plaque-targeting ITA-conjugated nanoparticles (ITA-LNPs) to investigate the effects of ITA on regulating lipid metabolism in foam cells/macrophages in atherosclerosis via ABCA1 stabilization and increased triglyceride metabolism.
Apoe mice were fed a high-cholesterol/high-fat diet (HCHFD) for 12 weeks and injected once weekly with 50 mg/kg ITA-LNP or Ctrl-LNP. Aortas were tested for ITA-LNP biodistribution, followed by quantification of atherosclerotic plaque burden. Bone marrow-derived macrophages (BMDMs) or RAW 264.7 cells were treated with ITA-LNP or Ctrl-LNP in the presence of oxLDL, acLDL, or free cholesterol to investigate ITA's actions on lipid metabolism, Abca1 expression, and ABCA1 stability under a variety of conditions, including stable gene knockdown.
ABCA1 was significantly upregulated with ITA-LNP treatment compared to Ctrl-LNP both in vivo and in vitro at the protein level, but not at the transcriptional level. ITA-LNPs were shown to prevent ABCA1 decay via the HO-1-calpain axis, resulting in significantly increased cholesterol efflux in macrophages. This was further confirmed in RAW 264.7 cells with a stable HO-1 knockdown. Additionally, ITA decreased lipid burden in conjunction with increased expression of Slc25a1 in ITA-LNP-treated BMDMs, suggesting enhanced fatty acid-derived citrate shuttling and increased fatty acid metabolism.
ITA-LNPs regulate lipid metabolism in atherosclerosis by inducing triglyceride catabolism and cholesterol efflux.
衣康酸（ITA）是三羧酸循环（TCA）产生的一种代谢产物，已被证明可通过免疫调节来调节动脉粥样硬化斑块的生长并诱导其稳定性。然而，目前在动脉粥样硬化中，ITA对脂质代谢的调节作用尚未得到充分研究。在此，我们利用靶向斑块的ITA偶联纳米颗粒（ITA-LNPs）来研究ITA通过稳定ABCA1和增加甘油三酯代谢对动脉粥样硬化中泡沫细胞/巨噬细胞脂质代谢的调节作用。
给Apoe小鼠喂食高胆固醇/高脂肪饮食（HCHFD）12周，每周注射一次50mg/kg的ITA-LNP或对照LNP（Ctrl-LNP）。检测主动脉中ITA-LNP的生物分布，随后对动脉粥样硬化斑块负荷进行定量分析。在氧化型低密度脂蛋白（oxLDL）、乙酰化低密度脂蛋白（acLDL）或游离胆固醇存在的情况下，用ITA-LNP或Ctrl-LNP处理骨髓来源的巨噬细胞（BMDMs）或RAW 264.7细胞，以研究ITA在多种条件下（包括稳定的基因敲低）对脂质代谢、Abca1表达和ABCA1稳定性的作用。
与Ctrl-LNP相比，ITA-LNP处理在体内和体外均使ABCA1蛋白水平显著上调，但在转录水平上无此现象。结果表明，ITA-LNPs通过HO-1-钙蛋白酶轴防止ABCA1降解，从而显著增加巨噬细胞中的胆固醇流出。在稳定敲低HO-1的RAW 264.7细胞中进一步证实了这一点。此外，ITA降低了脂质负荷，同时增加了ITA-LNP处理的BMDMs中Slc25a1的表达，提示脂肪酸衍生的柠檬酸穿梭增强和脂肪酸代谢增加。
ITA-LNPs通过诱导甘油三酯分解代谢和胆固醇流出，调节动脉粥样硬化中的脂质代谢。
