SCARB1 adenovirus

Homocysteine (Hcy) is an independent risk factor for atherosclerosis, which is characterized by the accumulation of lipids within atherosclerotic plaques. Increasing evidence suggests that scavenger receptor class B member 1 (SCARB1), as the main receptor for high-density lipoprotein, has a protective effect against atherosclerosis. However, its underlying mechanism in Hcy-mediated atherosclerosis is still unclear. Here, researchers found that the expression of SCARB1 was significantly inhibited in atherosclerotic plaques and Hcy-treated foam cells, while overexpression of SCARB1 could inhibit lipid accumulation in foam cells after Hcy treatment. Analysis of the SCARB1 promoter showed that the methylation level of the SCARB1 promoter did not change significantly under Hcy treatment in vivo and in vitro. In addition, the negative regulatory effect of DNMT3b on SCARB1 was due to the reduced recruitment of SP1 to the SCARB1 promoter. Therefore, DNMT3b-induced inhibition of SCARB1 expression accelerates Hcy-mediated atherosclerosis at least in part by promoting lipid accumulation in foam cells due to reduced SP1 binding to the SCARB1 promoter.

ApoE-/- mice carrying HHcy had a significant reduction in the number of SCARB1 puncta, as evidenced by reduced colocalization of SCARB1 with MOMA-2 in atherosclerotic plaques (Figure 1A). Consistent results were also observed at the mRNA and protein levels of SCARB1 in the aortas of ApoE-/- mice that received the same treatment, which was also confirmed in foam cells cultured in vitro (Figures 1B, C). These data suggest that Hcy may induce lipid deposition in foam cells by inhibiting the expression of SCARB1. To test this hypothesis, the researchers established a foam cell model with an adenoviral vector carrying SCARB1 (Ad-SCARB1). SCARB1 overexpression significantly reduced the total cholesterol (TC), cholesterol ester (CE), and TG (total triglyceride) content in Hcy-treated foam cells, but did not reduce the FC content (Figure 1D). However, knocking down SCARB1 obtained the opposite results (Figure 1E). Nile red staining showed that SCARB1 overexpression led to excess lipid bodies in foam cells in the presence of Hcy, further supporting that SCARB1 could attenuate Hcy-induced lipid accumulation (Figure 1F, G). Taken together, these data suggest that the increased lipid accumulation in Hcy-treated foam cells may be due to the downregulation of SCARB1 during atheromatous plaque formation.

Figure 1. Hcy promotes the accumulation of lipids in foam cells by the downregulation of SCARB1 expression. (Guo W, et al., 2020)