The role of Asialoglycoprotein Receptor-1 in Atherosclerosis

Simple item page
dc.contributor.advisorBursill, Christina
dc.contributor.advisorNicholls, Stephen (Monash University)
dc.contributor.advisorPacker, Nicole (Macquarie University)
dc.contributor.authorPullen, Benjamin James
dc.contributor.schoolAdelaide Medical Schoolen
dc.date.issued2023
dc.description.abstractCardiovascular diseases remain the single leading cause of death worldwide, of which atherosclerotic coronary artery disease (CAD) is the primary contributor [1]. Current treatment strategies target lipid levels to reduce the incidence of major adverse cardiovascular events (MACE). However, despite this, not all patients achieve their desired low density lipoprotein cholesterol (LDL-C) levels, and in those that do, there remains an unacceptably high level of residual risk of future events. Glycobiology, the study of glycans (i.e. sugars), offers a new lens with which to approach this, with the potential to identify new biomarkers and targets of CAD. Continual advances in the analytical techniques underpinning the field have greatly increased our understanding of these glycan structures and enabled the detailed characterisation of their myriad of functions in health and disease. The asialoglycoprotein receptor (ASGR) is a hepatic receptor that clears desialylated glycoproteins from the circulation. A loss-of-function mutation in the receptors primary subunit, ASGR-1, was shown to associate with a 34% reduction in CAD risk along with a 9% reduction in LDL-C levels and a 6% reduction in triglyceride levels [2]; highlighting a potential role for ASGR-1 in CAD. Recent evidence has also emerged suggesting that ASGR directly binds desialylated low density lipoproteins (LDL) [3,4]. The significance of the association between ASGR-1 and CAD was previously ascribed to enhanced degradation of the lowdensity lipoprotein receptor (LDLR). However, the expression of ASGR-1 on macrophages remains underexplored and its mechanisms of action poorly elucidated. This thesis set out to investigate the macrophage-related mechanisms for ASGR-1 and its role in atherosclerosis. This was achieved using macrophages derived from C57BL/6NJ and ASGR-1 deficient mice in a series of in vitro studies in conjunction with a newly derived Apoe -/- x Asgr1 -/- in vivo murine model to determine how ASGR-1 deficiency alters plaque progression and morphology, as well as macrophage biology, blood lipids and monocyte activation levels in an established model of atherosclerosis. This was supported by the first reported 2-dimensional mass spectrometry imaging of glycans in the aortic sinus, providing insights into the effect of ASGR-1 deletion on the N-glycome. We report that in vitro ASGR-1 is expressed on macrophages, that M2-like macrophages display the highest relative expression of ASGR-1 but reduced levels of ASGR-2, and that ASGR-1 deficiency causes athero-protective functions in macrophages; notably, increased cholesterol efflux from and decreased oxLDL uptake by ASGR-1 deficient macrophages. In vivo, we find that deletion of ASGR-1 causes a reduction in early-stage atherosclerosis in Apoe- /- mice on a high-cholesterol diet, albeit without changes in plaque composition. We also characterise the N-glycome of plaques from Apoe -/- x Asgr1 -/- mice and demonstrate that an altered distribution of N-glycans within their macrophage rich regions is associated with ASGR-1 deletion. In summary, these studies have provided valuable insights into the impact of ASGR-1 on the pathophysiology of atherosclerotic disease and opened new pathways with which to explore its direct role in plaque biology and the plaque glycome.en
dc.description.dissertationThesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2022en
dc.identifier.urihttps://hdl.handle.net/2440/139656
dc.language.isoenen
dc.provenanceThis electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at: http://www.adelaide.edu.au/legals en
dc.subjectAtherosclerosisen
dc.subjectglycoproteinen
dc.subjectglycobiologyen
dc.subjectasialoglycoprotein receptoren
dc.subjectASGRen
dc.subjectcoronary artery diseaseen
dc.titleThe role of Asialoglycoprotein Receptor-1 in Atherosclerosisen
dc.typeThesisen

Files

Original bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
Pullen2022_PhD.pdf
Size:
32.11 MB
Format:
Adobe Portable Document Format
Description:
Thesis
Download

Collections

Research Theses