ASGR1 Deficiency Inhibits Atherosclerosis in Western Diet–Fed ApoE −/− Mice by Regulating Lipoprotein Metabolism and Promoting Cholesterol Efflux

作者：Y. Zhang, Y. Zhang, Xinhai Jiang, Weizhi Wang, Lijuan Lei, Ren Sheng, Shunwang Li, Jinque Luo, Huan Liu, Jing Zhang, Xiaowan Han, Yining Li, Yuhao Zhang, Yuhao Zhang, Chenyin Wang, Shuyi Si, Zheng Gen Jin, Yanni Xu · 发表于：Arteriosclerosis Thrombosis and Vascular Biology · 年份：2024 · DOI：10.1161/atvbaha.124.321076 · 被引用次数：18 · 研究领域：Cholesterol and Lipid Metabolism、Diabetes, Cardiovascular Risks, and Lipoproteins、Cell Adhesion Molecules Research

BACKGROUND: Atherosclerosis is the most common cause of cardiovascular diseases. Clinical studies indicate that loss-of-function ASGR1 (asialoglycoprotein receptor 1) is significantly associated with lower plasma cholesterol levels and reduces cardiovascular disease risk. However, the effect of ASGR1 on atherosclerosis remains incompletely understood; whether inhibition of ASGR1 causes liver injury remains controversial. Here, we comprehensively investigated the effects and the underlying molecular mechanisms of ASGR1 deficiency and overexpression on atherosclerosis and liver injury in mice. METHODS: We engineered Asgr1 knockout mice ( Asgr1 −/− ), Asgr1 and ApoE double-knockout mice ( Asgr1 −/− ApoE −/− ), and ASGR1-overexpressing mice on an ApoE −/− background and then fed them different diets to assess the role of ASGR1 in atherosclerosis and liver injury. RESULTS: After being fed a Western diet for 12 weeks, Asgr1 −/− ApoE −/− mice exhibited significantly decreased atherosclerotic lesion areas in the aorta and aortic root sections, reduced plasma VLDL (very-low-density lipoprotein) cholesterol and LDL (low-density lipoprotein) cholesterol levels, decreased VLDL production, and increased fecal cholesterol contents. Conversely, ASGR1 overexpression in ApoE −/− mice increased atherosclerotic lesions in the aorta and aortic root sections, augmented plasma VLDL cholesterol and LDL cholesterol levels and VLDL production, and decreased fecal cholesterol contents. Mechanistically...