近日，英国剑桥大学Ziad Mallat及其研究组发现，早期间歇性高脂血症改变组织巨噬细胞来助推动脉粥样硬化。2024年9月4日，《自然》杂志在线发表了这项成果。

研究人员表示，高脂血症是动脉粥样硬化性心血管疾病（ASCVD）的主要危险因素。心血管事件的风险取决于终生累计暴露于低密度脂蛋白胆固醇（LDL-C）的程度，并且与LDL-C暴露的时间进程独立相关，早期暴露与较高的风险相关。此外，LDL-C的波动与ASCVD结局相关。然而，导致这种ASCVD风险增加的具体机制尚不清楚。

研究人员意外发现，与后期持续暴露于高胆固醇的西方型饮食（WD）相比，早期间歇性喂食WD会加速动脉粥样硬化，尽管累积的循环LDL-C水平相似。研究人员发现，早期间歇性高脂血症改变了类驻留动脉巨噬细胞的数量和稳态表型。表达发生改变的巨噬细胞基因在全基因组关联研究中与人类ASCVD相关基因富集。

研究人员表明，LYVE1⁺驻留巨噬细胞具有抗动脉粥样硬化的作用，并确定了与肌动蛋白丝组织相关的新生物通路，其改变会加速动脉粥样硬化。通过“芬兰年轻人研究”，研究人员发现早期暴露于胆固醇与中年时期颈动脉粥样硬化斑块的发生和大小显著相关。

总之，该研究表明，早期间歇性胆固醇暴露是加速动脉粥样硬化的重要决定因素，强调了早期优化控制高脂血症的重要性，并为潜在的生物学机制提供了见解。这一知识对于设计有效的治疗策略以对抗动脉粥样硬化性心血管疾病至关重要。

附：英文原文

Title: Early intermittent hyperlipidaemia alters tissue macrophages to fuel atherosclerosis

Author: Takaoka, Minoru, Zhao, Xiaohui, Lim, Hwee Ying, Magnussen, Costan G., Ang, Owen, Suffee, Nadine, Schrank, Patricia R., ONG, Wei Siong, Tsiantoulas, Dimitrios, Sommer, Felix, Mohanta, Sarajo K., Harrison, James, Meng, Yaxing, Laurans, Ludivine, Wu, Feitong, Lu, Yuning, Masters, Leanne, Newland, Stephen A., Denti, Laura, Hong, Mingyang, Chajadine, Mouna, Juonala, Markus, Koskinen, Juhani S., Khnen, Mika, Pahkala, Katja, Rovio, Suvi P., Mykknen, Juha, Thomson, Russell, Kaisho, Tsuneyasu, Habenicht, Andreas J. R., Clement, Marc, Tedgui, Alain, Ait-Oufella, Hafid, Zhao, Tian X., Nus, Meritxell, Ruhrberg, Christiana, Taleb, Soraya, Williams, Jesse W., Raitakari, Olli T., Angeli, Vronique, Mallat, Ziad

Issue&Volume: 2024-09-04

Abstract: Hyperlipidaemia is a major risk factor of atherosclerotic cardiovascular disease (ASCVD). Risk of cardiovascular events depends on cumulative lifetime exposure to low-density lipoprotein cholesterol (LDL-C) and, independently, on the time course of exposure to LDL-C, with early exposure being associated with a higher risk1. Furthermore, LDL-C fluctuations are associated with ASCVD outcomes2-4. However, the precise mechanisms behind this increased ASCVD risk are not understood. Here, we make the unexpected observation that early intermittent feeding of mice with a high-cholesterol Western-type diet (WD) accelerates atherosclerosis compared with late continuous exposure to WD, despite similar cumulative circulating LDL-C levels. We find that early intermittent hyperlipidaemia alters the number and homeostatic phenotype of resident-like arterial macrophages. Macrophage genes with altered expression are enriched for genes linked to human ASCVD in genome-wide association studies. We show that LYVE1+ resident macrophages are atheroprotective, and identify new biological pathways, related to actin filament organisation, whose alteration accelerates atherosclerosis. Using the Young Finns Study, we show that exposure to cholesterol early in life is significantly associated with the incidence and size of carotid atherosclerotic plaques in mid-adulthood. In summary, our results identify early intermittent exposure to cholesterol as a strong determinant of accelerated atherosclerosis, highlighting the importance of optimal control of hyperlipidaemia early in life, and providing insight into the underlying biological mechanisms. This knowledge will be essential to designing effective therapeutic strategies to combat atherosclerotic cardiovascular disease.

DOI: 10.1038/s41586-024-07993-x

Source: https://www.nature.com/articles/s41586-024-07993-x