Apolipoproteins E and CIII interact to regulate HDL metabolism and coronary heart disease risk
Allyson M. Morton, … , Majken K. Jensen, Frank M. Sacks
Allyson M. Morton, … , Majken K. Jensen, Frank M. Sacks
Published February 22, 2018
Citation Information: JCI Insight. 2018;3(4):e98045. https://doi.org/10.1172/jci.insight.98045.
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Clinical Medicine Metabolism

Apolipoproteins E and CIII interact to regulate HDL metabolism and coronary heart disease risk

Abstract

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.

Authors

Allyson M. Morton, Manja Koch, Carlos O. Mendivil, Jeremy D. Furtado, Anne Tjønneland, Kim Overvad, Liyun Wang, Majken K. Jensen, Frank M. Sacks

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Figure 9

Integrated model of HDL metabolism and epidemiology showing an adverse interaction between apoE and apoCIII.

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Integrated model of HDL metabolism and epidemiology showing an adverse i...
Left panel: The liver secretes HDL containing both apoE and apoCIII (E+CIII+) or HDL containing apoCIII but not apoE (E–CIII+) across a range of HDL sizes. These HDL subspecies do not experience significant size expansion that increases the size category. Upon arrival at the liver, either the lipids are cleared and prebeta generated, or the particles are cleared slowly from circulation (residence time: approximately 2.5 days). These HDL subspecies are associated with a higher risk of CHD. Right panel: The liver secretes HDL containing apoE but not apoCIII (E+CIII–) across a range of sizes. This HDL subspecies experiences size expansion from discoidal prebeta to larger α sizes, due to efflux of cholesterol from peripheral tissues. Upon arrival at the liver, either the lipids are cleared and prebeta generated, or the particles are cleared rapidly from the circulation (residence time: ~8 hours). This HDL subspecies is associated with a lower risk of CHD.