Apolipoproteins E and CIII interact to regulate HDL metabolism and coronary heart disease risk
Open accessAbstract
BACKGROUND. Subspecies of HDL contain apolipoprotein E (apoE) and/or apoCIII. Both proteins have properties that could affect HDL metabolism. The relation between HDL metabolism and risk of coronary heart disease (CHD) is not well understood. METHODS. Eighteen participants were given a bolus infusion of [D3]L-leucine to label endogenous proteins on HDL. HDL was separated into subspecies containing apoE and/or apoCIII and then into 4 sizes. Metabolic rates for apoA-I in HDL subspecies and sizes were determined by interactive modeling. The concentrations of apoE in HDL that contain or lack apoCIII were measured in a prospective study in Denmark including 1,949 incident CHD cases during 9 years. RESULTS. HDL containing apoE but not apoCIII is disproportionately secreted into the circulation, actively expands while circulating, and is quickly cleared. These are key metabolic steps in reverse cholesterol transport, which may protect against atherosclerosis. ApoCIII on HDL strongly attenuates these metabolic actions of HDL apoE. In the epidemiological study, the relation between HDL apoE concentration and CHD significantly differed depending on whether apoCIII was present. HDL apoE was associated significantly with lower risk of CHD only in the HDL subspecies lacking apoCIII. CONCLUSIONS. ApoE and apoCIII on HDL interact to affect metabolism and CHD. ApoE promotes metabolic steps in reverse cholesterol transport and is associated with lower risk of CHD. ApoCIII, when coexisting with apoE on HDL, abolishes these benefits. Therefore, differences in metabolism of HDL subspecies pertaining to reverse cholesterol transport are reflected in differences in association with CHD. TRIAL REGISTRATION. Clinicaltrials.gov NCT01399632. FUNDING. This work was supported by NIH grant R01HL095964 to FMS and by a grant to the Harvard Clinical and Translational Science Center (8UL1TR0001750) from the National Center for Advancing Translational Science.
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A similar inverse relationship between plasma ApoE level in HDL lacking ApoC3 and risk of coronary heart disease was reported in a large prospective population-based study.
“A similar inverse relationship between plasma ApoE level in HDL lacking ApoC3 and risk of coronary heart disease (CHD) was reported in a large prospective population-based study [32]”
From Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk (2023) · cites this paper as [32]
ApoE promotes metabolic steps in reverse cholesterol by rapidly clearing HDL from circulation when present on HDL in the absence of ApoC3, while coexisting ApoC3 with ApoE on HDL attenuates this beneficial effect on coronary heart disease.
“While ApoE promotes metabolic steps in reverse cholesterol by rapidly clearing HDL from circulation when present on HDL in the absence of ApoC3, coexisting of ApoC3 with ApoE on HDL attenuates this beneficial effect on CHD [32].”
From Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk (2023) · cites this paper as [32]
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- Authors
- Morton, A. M., Koch, M., Mendivil, C. O., Furtado, J. D., Tjønneland, A., Overvad, K., Wang, L., Jensen, M. K., & Sacks, F. M.
- Affiliations
- Harvard University (US)
- Danish Cancer Society (DK)
- Aarhus University (DK)
- Brigham and Women's Hospital (US)
- Corresponding author
- Sacks, Frank M.
- ORCID
- Venue
- JCI Insight
- Published
- 2018-02-22
- Volume
- 3
- Issue
- 4
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC5916256
- OpenAlex
- W2788395983
- Cited by
- 91
- References
- 9
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 7 · 2023: 12 · 2022: 15 · 2021: 11 · 2020: 14 · 2019: 8 · 2018: 4
- FWCI
- 9.62
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- JCI Insight (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- VBN Forskningsportal (Aalborg Universitet) (submittedVersion, other-oa)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- National Institutes of Health (R01HL095964)
- National Center for Advancing Translational Sciences (8UL1TR0001750)
- Deutsche Forschungsgemeinschaft (KO 5187/1-1)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
- Keywords
- apolipoprotein E, apolipoprotein C-III, HDL metabolism, HDL subfractions, reverse cholesterol transport, coronary heart disease risk, HDL size, apolipoprotein A-I, atherosclerosis
- MeSH terms
- Adult, Aged, Apolipoproteins E, Cholesterol, Coronary Disease, Denmark, Female, Humans, Lipoproteins, HDL, Male, Middle Aged, Prospective Studies, Protein Binding, Incidence, Case-Control Studies, Apolipoprotein A-I, Atherosclerosis, Apolipoprotein C-III, Young Adult
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