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 6

Interaction between apoE and apoCIII on HDL.

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Interaction between apoE and apoCIII on HDL. Model fit for apoA-I tracer...
Model fit for apoA-I tracer enrichments and apoA-I FCRs (pools/day) in 4 HDL subspecies each separated into 4 HDL sizes (n = 10). (A) Model fit and mean tracer enrichments. The % D3-leucine tracer enrichments (D3-leucine/[D3-leucine + unlabeled leucine] × 100) were computed by averaging all participants’ enrichments (n = 10) at each time point and modeling them as a single participant. The bare-minimum model, as shown in Figure 2A, was used for E–CIII–, E–CIII+, and E+CIII+. The complex model, as shown in Figure 2B, was used for E+CIII– only. (B) ApoA-I fractional catabolic rates, representing protein turnover. Each point represents a single participant (n = 10). A value of 1 = 100% of protein pool turned over per day. Error bars ± SEM. Within each HDL size, different letters above each bar refer to statistically different mean values (P < 0.005 vs. all other subspecies as assessed by mixed effects model). Specifically, the FCR of E+CIII– subspecies in each size is significantly faster than that of the other subspecies, whereas the FCR of E+CIII+ is not significantly higher, suggesting an interaction between the 2 apolipoproteins on HDL. One outlier is not shown for visual purposes (E+CIII– prebeta, value 31 pools/day) but was included in the statistical analysis.