Department of Medicine, Columbia University, New York, NY, USA.
Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Adv Exp Med Biol. 2020;1276:67-83. doi: 10.1007/978-981-15-6082-8_6.
Most types of cells in the body have no or very limited capacity of catabolizing cholesterol, so cholesterol efflux is essential for cholesterol homeostasis. There are multiple mechanisms responsible for cellular cholesterol efflux. Among them, the active efflux pathways are mediated primarily by the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1. ABCA1 is essential for cholesterol and phospholipid efflux to apolipoprotein A-I and high density lipoprotein (HDL) biogenesis. ABCG1 promotes cholesterol efflux primarily to HDL particles. Atherosclerotic cardiovascular disease is a chronic inflammatory disease characterized by marked macrophage foam cell accumulation in atherosclerotic plaques and associated pro-inflammatory responses in lesional cells. Findings from both animal and human studies indicate a critical role of disturbed cholesterol homeostasis in pro-inflammatory responses in these cells, particularly in lesional macrophages. ABCA1 and ABCG1 are highly expressed in macrophages, particularly in response to cholesterol accumulation, and are essential in maintenance of cholesterol homeostasis. Functional deficiency of ABCA1 and ABCG1 in macrophage markedly increases atherogenesis, with exacerbated inflammatory responses. ABCA1 and ABCG1 also play a critical role in control of hematopoietic stem and progenitor cell (HSPC) proliferation and extramedullary hematopoiesis. Hematopoietic ABCA1 and ABCG1 deficiencies cause marked HSPC expansion and extramedullary hematopoiesis, particularly in hypercholesterolemia, and lead to marked monocytosis and neutrophilia with exacerbated pro-inflammatory responses. All these contribute to atherosclerosis. In this chapter, we describe these findings and discuss the current understanding of the underlying mechanisms. We also discuss other ABC transporters such as ABCG4, which also promotes cholesterol efflux to HDL and controls megakaryocyte proliferation and platelet biogenesis. By this pathway, ABCG4 also modulates atherogenesis. Therapeutic approaches targeting the pathways and mechanisms described also are discussed.
体内大多数细胞几乎没有或仅有有限的胆固醇代谢能力，因此胆固醇外排对于胆固醇稳态至关重要。有多种机制负责细胞胆固醇外排。其中，主动外排途径主要由 ATP 结合盒（ABC）转运蛋白 ABCA1 和 ABCG1 介导。ABCA1 对于胆固醇和磷脂向载脂蛋白 A-I 和高密度脂蛋白（HDL）生成的外排以及 HDL 的生成至关重要。ABCG1 主要促进胆固醇向 HDL 颗粒的外排。动脉粥样硬化性心血管疾病是一种慢性炎症性疾病，其特征是动脉粥样斑块中明显的巨噬细胞泡沫细胞积聚以及病变细胞中的促炎反应。动物和人类研究的结果表明，胆固醇稳态失调在这些细胞的促炎反应中起着关键作用，特别是在病变的巨噬细胞中。ABCA1 和 ABCG1 在巨噬细胞中高表达，特别是在胆固醇积累时，对于维持胆固醇稳态至关重要。巨噬细胞中 ABCA1 和 ABCG1 的功能缺陷会显著增加动脉粥样硬化的发生，加剧炎症反应。ABCA1 和 ABCG1 在控制造血干细胞和祖细胞（HSPC）增殖和骨髓外造血中也起着关键作用。HSPC 中的 ABCA1 和 ABCG1 缺陷会导致明显的 HSPC 扩增和骨髓外造血，特别是在高胆固醇血症中，导致单核细胞和中性粒细胞明显增加，促炎反应加剧。所有这些都促成了动脉粥样硬化。在本章中，我们描述了这些发现，并讨论了潜在机制的当前理解。我们还讨论了其他 ABC 转运蛋白，如 ABCG4，它也促进胆固醇向 HDL 的外排，并控制巨核细胞增殖和血小板生成。通过这条途径，ABCG4 也调节动脉粥样硬化的发生。还讨论了针对所描述的途径和机制的治疗方法。
