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 2

ApoA-I metabolism on 4 sizes of HDL (n = 18).

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ApoA-I metabolism on 4 sizes of HDL (n = 18). (A) Mean pool size of plas...
(A) Mean pool size of plasma apoA-I for 4 sizes of HDL, calculated from SDS-PAGE band densitometry corrected to plasma apoA-I concentrations measured by ELISA. Error bars ± SEM. Numbers above bars show mean percent plasma apoA-I distribution across HDL sizes. (B) Compartmental model used in SAAM-II with the greatest parsimony (bare-minimum model). Plasma D3-leucine enrichment, the precursor to protein synthesis, is modeled as a forcing function (FF) input to the liver or intestine (“Source” compartment). Circles represent each HDL size (from large to small: a1 = α-1, a2 = α-2, a3 = α-3, preB = prebeta). Arrows between compartments represent transfer of apoA-I. Arrows out of compartments represent clearance of apoA-I from plasma. The rectangle with interior circles represents an intravascular delay compartment used for synthesis, assembly, and secretion of apoA-I. The gray circle represents a nonsampled remodeling compartment to generate prebeta HDL from α-3 HDL, such as by the action of SR-B1 or hepatic TG lipase. (C) SAAM-II model fit of mean tracer enrichment in HDL apoA-I for each HDL size. The tracer enrichments were generated by averaging all participants’ enrichments at each time point. (D) SAAM-II model fit of mean apoA-I mass (pool size) for each HDL size. The masses were the averages of all participants’ masses at each time point. Masses were measured from SDS-PAGE band densitometry corrected to plasma apoA-I concentrations measured by ELISA. (E) Mean apoA-I fractional catabolic rates (representing protein turnover) for each HDL size. A value of 0.4 represents 40% of the protein pool turned over each day. Each dot represents a single participant. Error bars ± SEM.