SR-BI: A Multifunctional Receptor in Cholesterol Homeostasis and Atherosclerosis

Abstract

The HDL receptor scavenger receptor class B type I (SR-BI) plays crucial roles in cholesterol homeostasis, lipoprotein metabolism, and atherosclerosis. Hepatic SR-BI mediates reverse cholesterol transport (RCT) by the uptake of HDL cholesterol for routing to the bile. Through the selective uptake of HDL lipids, hepatic SR-BI modulates HDL composition and preserves HDL's atheroprotective functions of mediating cholesterol efflux and minimizing inflammation and oxidation. Macrophage and endothelial cell SR-BI inhibits the development of atherosclerosis by mediating cholesterol trafficking to minimize atherosclerotic lesion foam cell formation. SR-BI signaling also helps limit inflammation and cell death and mediates efferocytosis of apoptotic cells in atherosclerotic lesions thereby preventing vulnerable plaque formation. SR-BI is emerging as a multifunctional therapeutic target to reduce atherosclerosis development.

Figure 1. Hepatic SR-BI: Selective Uptake of HDL Lipids Regulates HDL Function

Hepatic SR-BI mediates the selective uptake of HDL lipids including cholesteryl ester (CE) and lipid hydroperoxides (LOOH), thereby modulating HDL composition and function. Loss of hepatic SR-BI function results in the accumulation of enlarged, dysfunctional HDL in plasma. The cholesterol-enriched HDL has reduced capacity to promote the net efflux of cholesterol from macrophages. The HDL has increased LOOH content and decreased PON1 activity thereby reducing its anti-oxidative function. The enlarged HDL particle is impaired in mediating pro-survival and anti-inflammatory signaling. The reduced ability of enlarged HDL to remove cholesterol from cells results in platelets that are cholesterol engorged and prothrombotic.

Figure 2. SR-BI Functions in Preventing Macrophage Foam Cell Formation by Mobilizing Cholesterol

Macrophages have three major proteins that mediate the efflux of free cholesterol (FC) including SR-BI, ABCA1, and ABCG1. SR-BI and ABCG1 efflux cholesterol to HDL, whereas ABCA1 transports phospholipid and cholesterol to plasma-derived lipid-poor apoAI or to apoE that is secreted by macrophages. In human macrophages, ABCA1 and SR-BI are the main cholesterol efflux pathways. Cytoplasmic cholesteryl ester (CE) is cleared by two pathways: 1) CE can be hydrolyzed by neutral CE hydrolase (NCEH) and the FC trafficked to the plasma membrane for efflux: 2) Cytoplasmic CE is also packaged into autophagosomes that fuse with lysosomes, where the CE is hydrolyzed by lysosomal acid lipase and the FC trafficked for release from the cell.

Figure 3. SR-BI Regulates Macrophage Inflammation, Apoptosis, and Efferocytosis

In response to stressors such as oxidized LDL and inflammatory cytokines, NF-κB is activated thereby enhancing the transcription of proinflammatory cytokines (i.e. IL-1β, TNF-α, and IL-6). Ligands that bind SR-BI including HDL, PON1, apoptotic cells, and sphingosine 1-phosphate reduce the inflammatory response by activating Akt and reducing activation of NF-κB leading to increased secretion of anti-inflammatory IL-10 and TGF-β. When SR-BI signaling and activation of Akt is compromised, the enhanced production of inflammatory cytokines and reactive oxygen species (ROS) promotes apoptosis. Macrophage SR-BI mediates the efferocytosis of apoptotic cells via Src/PI3K/Akt/Rac1 signaling, leading to phagocyte survival and an anti-inflammatory response. Impaired efferocytosis via SR-BI promotes secondary necrosis, phagocyte death, and unresolved inflammation promoting formation of the atherosclerotic vulnerable plaque. MΦ, macrophage; PS, phosphatidylserine; AC, apoptotic cells.