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

Oct 10, 2024Arteriosclerosis, thrombosis, and vascular biology

ASGR1 Deficiency May Reduce Artery Disease in High-Fat Diet Mice by Changing Fat Metabolism and Helping Remove Cholesterol

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Abstract

Mice lacking showed significantly decreased atherosclerotic lesion areas after 12 weeks on a Western diet.

ASGR1 deficiency is associated with reduced plasma VLDL and LDL cholesterol levels.
Decreased VLDL production and increased fecal cholesterol contents were observed in ASGR1-deficient mice.
Inhibition of ASGR1 appears to enhance LDL uptake and promote cholesterol efflux through various mechanisms.
Conversely, ASGR1 overexpression led to increased atherosclerotic lesions and higher VLDL and LDL cholesterol levels.
ASGR1 deficiency may worsen liver injury in certain dietary conditions, while its overexpression may have a protective effect.

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BACKGROUND: is the most common cause of cardiovascular diseases. Clinical studies indicate that loss-of-function (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 engineeredknockout mice (),anddouble-knockout mice (), and ASGR1-overexpressing mice on anbackground and then fed them different diets to assess the role of ASGR1 in atherosclerosis and liver injury. Asgr1Asgr1Asgr1ApoE Asgr1ApoE ApoE -/--/--/--/-

RESULTS: After being fed a Western diet for 12 weeks,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 inmice 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-overexpressingmice. In addition, ASGR1 deficiency exacerbates liver injury in Western diet-inducedmice and high-fat diet-induced but not normal laboratory diet-induced and high-fat and high-cholesterol diet-inducedmice, while its overexpression mitigates liver injury in Western diet-induced ASGR1-overexpressingmice. Asgr1ApoE ApoE ApoE Asgr1ApoE Asgr1ApoE -/--/--/--/--/--/--/--/-

CONCLUSIONS: Inhibition of ASGR1 inhibits atherosclerosis in Western diet-fedmice, suggesting that inhibiting ASGR1 may serve as a novel therapeutic strategy to treat atherosclerosis and cardiovascular diseases. ApoE -/-

Key numbers

78.53%

Decrease in Atherosclerotic Lesions

Observed in female -deficient mice fed a Western diet.

36.07±2.86×10μm

Increase in Atherosclerotic Lesions

Measured in aortic root sections of -overexpressing mice.

39.46%

VLDL Production Increase

Measured after administration of a lipase inhibitor.

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

Abstract

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