Early intermittent hyperlipidaemia alters tissue macrophages to fuel atherosclerosis

• Published in: Nature (London) Vol. 634; no. 8033; pp. 457 - 465
• Main Authors: 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., Kähönen, Mika, Pahkala, Katja, Rovio, Suvi P., Mykkänen, 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, Véronique, Mallat, Ziad
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.10.2024; Nature Publishing Group
• Subjects: 13; 13/1; 13/51; 14/19; 631/443; 631/443/592; 64; Actin; Antibiotics; Arteriosclerosis; Atherosclerosis; Autophagy; Biological effects; Cardiovascular disease; Cardiovascular diseases; Cholesterol; Experiments; Exposure; Genes; Genome-wide association studies; Health risks; High cholesterol diet; Humanities and Social Sciences; Hyperlipidemia; Low density lipoprotein; Macrophages; Microbiota; multidisciplinary; Optimal control; Phenotypes; Plasma; Risk factors; Science; Science (multidisciplinary)
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-024-07993-x

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 risk 1 . Furthermore, LDL-C fluctuations are associated with ASCVD outcomes 2 – 4 . However, the precise mechanisms behind this increased ASCVD risk are not understood. Here we find that early intermittent feeding of mice on a high-cholesterol Western-type diet (WD) accelerates atherosclerosis compared with late continuous exposure to the 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 biological pathways related to actin filament organization, of which 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 insights into the underlying biological mechanisms. This knowledge will be essential to designing effective therapeutic strategies to combat ASCVD. Early intermittent feeding of mice with a high-cholesterol Western-type diet accelerates atherosclerosis compared with late continuous exposure to the Western-type diet, despite similar cumulative circulating LDL-C levels.