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

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, ASGR1 deficiency reduced VLDL production by inhibiting the expression of MTTP (microsomal triglyceride transfer protein) and ANGPTL3 (angiopoietin-like protein 3)/ANGPTL8 (angiopoietin-like protein 8) but increasing LPL (lipoprotein lipase) activity, increased LDL uptake by increasing LDLR (LDL receptor) expression, and promoted cholesterol efflux through increasing expression of LXRα (liver X receptor-α), ABCA1 (ATP-binding cassette subfamily A member 1), ABCG5 (ATP-binding cassette subfamily G member 5), and CYP7A1 (cytochrome P450 family 7 subfamily A member 1). These underlying alterations were confirmed in ASGR1-overexpressing ApoE −/− mice. In addition, ASGR1 deficiency exacerbates liver injury in Western diet–induced Asgr1 −/− ApoE −/− mice and high-fat diet–induced but not normal laboratory diet–induced and high-fat and high-cholesterol diet–induced Asgr1 −/− mice, while its overexpression mitigates liver injury in Western diet–induced ASGR1-overexpressing ApoE −/− mice. CONCLUSIONS: Inhibition of ASGR1 inhibits atherosclerosis in Western diet–fed ApoE −/− mice, suggesting that inhibiting ASGR1 may serve as a novel therapeutic strategy to treat atherosclerosis and cardiovascular diseases.