Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.
Nat Commun. 2021 Jul 21;12(1):4434. doi: 10.1038/s41467-021-24684-7.
Dyslipidemia is a main driver of cardiovascular diseases. The ability of macrophages to scavenge excess lipids implicate them as mediators in this process and understanding the mechanisms underlying macrophage lipid metabolism is key to the development of new treatments. Here, we investigated how adipose tissue macrophages regulate post-prandial cholesterol transport. Single-cell RNA sequencing and protected bone marrow chimeras demonstrated that ingestion of lipids led to specific transcriptional activation of a population of resident macrophages expressing Lyve1, Tim4, and ABCA1. Blocking the phosphatidylserine receptor Tim4 inhibited lysosomal activation and the release of post-prandial high density lipoprotein cholesterol following a high fat meal. Both effects were recapitulated by chloroquine, an inhibitor of lysosomal function. Moreover, clodronate-mediated cell-depletion implicated Tim4 resident adipose tissue macrophages in this process. Thus, these data indicate that Tim4 is a key regulator of post-prandial cholesterol transport and adipose tissue macrophage function and may represent a novel pathway to treat dyslipidemia.
血脂异常是心血管疾病的主要驱动因素。巨噬细胞清除多余脂质的能力使它们成为这一过程的中介，了解巨噬细胞脂质代谢的机制是开发新治疗方法的关键。在这里，我们研究了脂肪组织巨噬细胞如何调节餐后胆固醇转运。单细胞 RNA 测序和受保护的骨髓嵌合体表明，脂质的摄入导致表达 Lyve1、Tim4 和 ABCA1 的常驻巨噬细胞群体的特定转录激活。阻断磷脂酰丝氨酸受体 Tim4 可抑制高脂肪餐后溶酶体的激活和餐后高密度脂蛋白胆固醇的释放。氯喹（一种溶酶体功能抑制剂）可再现这两种作用。此外，氯膦酸盐介导的细胞耗竭使 Tim4 驻留的脂肪组织巨噬细胞参与了这一过程。因此，这些数据表明 Tim4 是餐后胆固醇转运和脂肪组织巨噬细胞功能的关键调节剂，可能代表治疗血脂异常的新途径。
