Mechanisms underlying the atherosclerosis risk associated with apolipoprotein E isoforms in humans Public Deposited

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Last Modified
  • March 21, 2019
Creator
  • Altenburg, Michael Kelly
    • Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
Abstract
  • Apolipoprotein E (apoE) is a ligand for the low density lipoprotein receptor (LDLR), both of which are well recognized determinants of atherosclerosis risk in humans. In humans the APOE gene is polymorphic, with three alleles APOE2, APOE3, and APOE4 coding for the protein apoE2, apoE3, and apoE4. Despite increased LDLR affinity, apoE4 is associated with elevated and apoE2 reduced cholesterol concentration compared to apoE3. Mice that have had their endogenous apoE replaced with the human apoE's do not replicate their human counterparts, and mice with apoE3 and apoE4 are similar to wildtype mice, yet those with apoE2 have drastically elevated lipids, a phenotype observed in only 5% of APOE2 homozygous humans. Either by adenovirus-mediated or global overexpression, elevated LDLR decreased plasma cholesterol in mice with apoE2, but led to a dramatic accumulation of cholesterol-rich VLDL in mice with apoE4 on a western-type high fat diet. In addition to the liver, where both apoE and LDLR are highly expressed and contribute to plasma lipoprotein clearance, they are expressed in vascular cells and macrophages. Increases in LDLR expression in macrophages significantly increased cholesterol uptake in culture, more prominently with lipoproteins containing apoE4 than those containing apoE3. In LDLR-deficient mice expressing the human apoE4 isoform, the replacement of bone marrow cells with those expressing LDLR increased atherosclerotic lesions in a dose-dependent manner compared with mice transplanted with cells having no LDLR. Thus apoE4, but not apoE3, in macrophages enhances atherosclerotic plaque development in mice in an LDLR-dependent manner and this interaction may contribute to the association of apoE4 with an increased cardiovascular risk in humans. Higher LDLR expression decreased the secretion of apoE4 and increased its degradation in both macrophages and hepatocytes. ApoE localization using apoE-GFP fusion proteins expressed by adenovirus in the liver of apoE-deficient mice revealed that apoE4 accumulated in the space of Disse, but apoE2 did not. Using several genetic approaches, apoE4s association with increased atherosclerosis risk can be replicated in mice. ApoE4 binding to the LDLR in macrophages and localization in hepatocytes both contribute to apoE4 pathogenesis.
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  • In Copyright
Advisor
  • Maeda, Nobuyo
Degree granting institution
  • University of North Carolina at Chapel Hill
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  • Open access
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