Peripheral cells acquire cholesterol through lipoprotein uptake and synthesis, yet most lack cholesterol catabolism mechanisms. While some cells like steroid hormone producers, intestinal cells, and skin cells can eliminate cholesterol, the majority rely on reverse cholesterol transport to manage cholesterol levels. This process is particularly significant in preventing atherosclerosis, as efficient cholesterol efflux from arterial wall macrophages is crucial.
A key player in this Lipid Transport process is ABCA1, facilitating cholesterol efflux to lipid-poor pre-beta Apo A-I particles (Figure 1). ABCG1 also plays a vital role, mediating cholesterol transfer to mature HDL particles. SR-B1 and passive diffusion may also contribute to cholesterol efflux to HDL. The expression of both ABCA1 and ABCG1 is upregulated by LXR activation, a nuclear hormone receptor activated by oxysterols. Increased cellular cholesterol leads to oxysterol formation, activating LXR and subsequently enhancing ABCA1 and ABCG1 expression, thereby promoting cholesterol efflux.
Furthermore, ABCA1 and ABCG1 mRNAs are regulated by miR-33, a microRNA within the SREBP2 gene. Elevated cellular cholesterol reduces SREBP2 expression, decreasing miR-33 and enhancing LXR expression. This dual effect of reduced SREBP2—decreasing LDL receptor activity (reducing cholesterol uptake) and decreasing miR-33 (increasing cholesterol efflux)—contributes to cellular cholesterol homeostasis. Conversely, low cellular cholesterol increases SREBP2 and miR-33, reducing LXR activity and cholesterol efflux, while increasing cholesterol uptake. This coordinated regulation of uptake and efflux, mediated by the LDL receptor, ABCA1, and ABCG1, is essential for maintaining cellular cholesterol balance within the broader context of lipid transport.
Figure 1. Cholesterol Efflux from Macrophages
Once cholesterol moves from cells to HDL, two pathways facilitate its transport to the liver for elimination, a critical step in systemic lipid transport. First, HDL can interact with hepatic SR-BI receptors, enabling selective cholesterol uptake. Second, CETP can transfer cholesterol from HDL to Apo B-containing particles, which are then taken up by the liver. In the liver, cholesterol can be converted into bile acids for secretion or directly secreted into bile. ABCG5 and ABCG8 enhance cholesterol transport into bile, and their gene expression is also boosted by LXR activation. Therefore, increased hepatic cholesterol, leading to oxysterol production, activates LXR, increasing ABCG5 and ABCG8 expression and promoting cholesterol secretion into bile, completing the lipid transport pathway.
The efficiency of reverse cholesterol transport, a vital component of overall lipid transport, is recognized as a protective mechanism against atherosclerosis. It’s important to note that HDL cholesterol levels alone may not fully reflect the rate of reverse cholesterol transport. This process is complex, involving multiple steps, and HDL cholesterol levels might not accurately represent each stage. Studies indicate that HDL’s ability to promote cholesterol efflux from macrophages can vary, meaning identical HDL cholesterol levels may have differing capacities to initiate reverse cholesterol transport. Therefore, a comprehensive understanding of lipid transport and its reverse cholesterol component is crucial for assessing cardiovascular health beyond just measuring HDL cholesterol concentrations.
