ABCG1 can increase cholesterol efflux, help cells to eliminate excess cholesterol and avoid accumulation of cholesterol in cells. It was found that ABCG1 binds to cholesterol and sphingomyelin at different binding sites and there may be synergistic interactions between these binding sites. At the same time, ABCG1 is not specific for receptors that transport cholesterol to the outside of cells. It regulates the outflow of intracellular cholesterol to LDL, HDL, and lack of protein phospholipid vesicles, indicating that ABCG1 regulates cholesterol efflux and does not depend on an extracellular specific interaction between protein and membrane.
Daniil et al. found that when the structure of the major apolipoprotein ApoA-1 peptide chain was changed, the ability of HDL to affect the translocation of ABCG1 to extracellular cholesterol was affected. Studies have confirmed that the existence of pit cells in the cell membrane and Golgi complex is the main protein that mediates cell cholesterol efflux. Gu et al. found that ABCG1 can regulate cholesterol efflux by interacting with foveolin-1. Freeman et al. reported that ABCG1 not only regulates cholesterol reverse transport on the cell surface but also regulates the production of extracellular cholesterol microdomains and plays an important role in the extracellular region.
Xue et al. showed that the expression of ABCG1 in human umbilical artery endothelial cells (HUAEC) is silenced in endothelial cells by small interference RNA (siRNA), which leads to a decrease in cholesterol outflow to HDL and an increase in intracellular cholesterol, resulting in increased expression of endoplasmic reticulum stress molecules, and endothelial cell apoptosis.
Another study found that ABCG1 expression in a variety of cells in diabetic mouse model decreased. ABCG1-regulated cholesterol efflux is severely impaired in patients with type 2 diabetes, and decreased expression of ABCG1 in pancreatic islet β cells, leading to decreased insulin secretion. However, when chronic inflammation occurs in the small intestine of type 2 diabetic rats, the expression of ABCG1 in inflammatory cells increases, and its specific role remains to be further studied.
Macrophages take up oxidized low-density lipoprotein (LDL) and then convert it into foam cells to promote the formation of atheromatous plaques. The key factors of cholesterol in the inflammatory pathway of atherosclerosis are increasingly valued. Lang et al. found that cholesterol can promote the release and proliferation of peripheral blood from hematopoietic stem cells and promote its differentiation into inflammatory cells such as mononuclear and neutrophils, then participating in the formation of atherosclerosis. The regulation of cholesterol efflux by ABCG1 plays an important role in the development of atherosclerosis.
Earlier studies have shown that ABCG1 plays a key role in the outflow of cholesterol to HDL, and its activation or overexpression leads to an increase in intracellular cholesterol efflux. According to this conclusion, if ABCG1 is deleted from the macrophages, it will lead to a decrease in cholesterol efflux, promote the formation of foam cells, and eventually lead to an increase in atherosclerosis. However, this conclusion is still controversial.
It has been reported that, under similar experimental conditions, there was a slight increase in atherosclerosis, which the researchers believe is the result of impaired cholesterol efflux. The researchers then constructed ABCG1-/- Apoe-/- double knockout mice and found that the atherosclerotic lesions were reduced and the apoptosis of macrophages in injury place is increased in the double knockout mice compared to Apoe-/- mice. Another study of bone marrow transplantation using ABCG1-/- Apoe-/- double knockout mice as donors and Apoe-/- mice as recipients showed that the absence of ABCG1 in macrophages was sufficient for reducing the injury of atherosclerosis.
To further investigate the mechanism of action in the atherosclerotic process of ABCG1, the researchers fed ABCG1-/-/Ldlr-/- double knockout mice and Ldlr-/- knockout mice on a high-fat diet. There was no significant difference in the size of atherosclerotic lesions between the two groups at the 12th week of feeding, but after the 23rd week, the atherosclerotic lesions in the Abcg1-/-/Ldlr-/- double knockout mice were significantly larger than the other groups. Another study reported that after 10 weeks of high-fat diet, atherosclerotic lesion area was 1.5 times that of Ldlr-/- single gene knockout group, and it increased 1.7 times after 12 weeks. Although the above results do not fully elucidate the mechanism of action of ABCG1 in the development of atherosclerosis, it is suggested that the effect of ABCG1 may be related to the stage of atherosclerosis formation. In the early stage of plaque formation, ABCG1 has a potential protective effect, but in the late stage. ABCG1 may promote plaque formation.
The risk of developing the atherosclerotic disease in diabetic patients is significantly increased. It is of great significance to investigate the pathogenesis of atherosclerosis in diabetic patients. Spartano et al. found that bone marrow-derived macrophages can reduce HDL-mediated cholesterol efflux by inhibiting ABCG1 activity in high glucose state, suggesting that this high cholesterol-induced cholesterol efflux injury may promote the development of diabetes-related atherosclerosis.