Project 461769

Cardiometabolic disease (CMD) consists of several modifiable risk factors such as diabetes, obesity and lipids that can lead to a heart attack or stroke and accounts for the majority of deaths in North America. CMD drives atherosclerosis, the underlying cause of heart disease. Recent hallmark studies have shown that individuals with loss-of-function genetic mutations in either PCSK9 or asialoglycoprotein receptor 1 (ASGR1) cause a significant reduction in LDL cholesterol (LDLc) and protect against CVD. PCSK9 is a circulating blood factor that binds to and regulates the levels of the LDL receptor on the liver. ASGR1 is a receptor expressed on the liver surface which can bind and remove plasma proteins via modified sugar residues. We have now discovered that removing ASGR1 from liver cells increases LDL receptor levels and causes a modest reduction in LDLc, a driver of CMD. This effect is independent of PCSK9. Our study proposes to investigate how ASGR1/2 contributes to CMD and atherosclerosis, both in the absence or presence of PCSK9. We plan to use established genetic, cellular and molecular approaches to determine whether ASGR1/2 forms a complex with the LDL receptor to affect its expression or activity. In addition, relevant mouse models will be used to determine whether deficiency in ASGR1/2 alone or with PCSK9 act in concert to reduce CMD and/or atherosclerosis. Finally, we will determine whether the soluble form of ASGR1 found in blood contributes CMD and atherosclerosis. These studies are important because they will provide a better understanding of how PCSK9 and ASGR1 regulate so that novel therapies aimed at reducing the risk of CMD can be developed.