The LOX-1 Receptor Ectopically Expressed in the Liver Alleviates Atherosclerosis by Clearing Ox-LDL in the Circulation
Abstract Objective: Ox-LDL is the core factor in the development of atherosclerosis. However, there are few therapyaimed at eliminating Ox-LDL. Here in this study, we investigate whether the expression of the lectin-like oxidized low density lipoprotein receptor (LOX-1) in the liver could lead to the phagocytosis and degradationof circulating Ox-LDL and prevent the deposition of oxidized lipids in the vascular wall, thereby alleviatingthe progression of atherosclerosis.Methods: ApoE-/- mice were randomly divided into three groups, the control group,the AAV8-TBG-eGFP group and AAV8-TBG-LOX-1 group. In the viral group, mice received an injection of AAV8-TBG-LOX-1 (1.16×1011 virus genome (vg)/animal/100 μl). The mice in the control group and the AAV8-TBG-eGFP group received the same amount of sterile saline and AAV8-TBG-eGFP injections. The expression of LOX-1 in the liver was detected by immunofluorescent, Western blot and immunohistochemistry. The safety was assessed by H&E staining and blood biochemical analyses. The function of LOX-1 in the liver was detected by the co- localization of LOX-1 and Dil-Ox-LDL under laser scanning confocal microscope. The Ox-LDL in plasma was detected by ELISA. Changes in blood lipids were assessed through blood biochemical analysis. The pro- gression of atherosclerotic lesions was detected by oil red O(ORO) staining. And the expression of VCAM- 1 in endothelial cells and the extent of macrophages in plaques were detected by immunofluorescence staining. The protein expression in liver was assessed by qRT-PCR and Western blot. Results: The expression of LOX-1 was stable in liver within 4 weeks. Ectopically expressed LOX-1 in the liver phagocytosed and degraded Ox-LDL and reduced Ox-LDL in circulating plasma but did not have a significant effect on blood lipid levels. After the expression of LOX-1 in liver, Ox-LDL can be cleared by the liver, thereby reducing VCAM-1 expression in vascular endothelium and migration of macrophages in plaques, and eventually alleviating the progression of atherosclerosis. Hepatic LOX-1 expression may facilitate the metabolic clearance of Ox-LDL by upregulating the expression of ABCG5/G8. Conclusions: Ectopic liver-specific expression of LOX-1 alleviates the progression of atherosclerosis by clearing Ox-LDL in circulation.