Apolipoprotein E content of VLDL limits LPL-mediated triglyceride hydrolysis

Brynne E Whitacre,Philip Howles,Scott Street,Jamie Morris,Debi Swertfeger,W Sean Davidson

doi:10.1016/j.jlr.2021.100157

Abstract

High levels of circulating triglycerides (TGs), or hypertriglyceridemia, are key components of metabolic diseases, such as type 2 diabetes, metabolic syndrome, and CVD. As TGs are carried by lipoproteins in plasma, hypertriglyceridemia can result from overproduction or lack of clearance of TG-rich lipoproteins (TRLs) such as VLDLs. The primary driver of TRL clearance is TG hydrolysis mediated by LPL. LPL is regulated by numerous TRL protein components, including the cofactor apolipoprotein C-II, but it is not clear how their effects combine to impact TRL hydrolysis across individuals. Using a novel assay designed to mimic human plasma conditions in vitro, we tested the ability of VLDL from 15 normolipidemic donors to act as substrates for human LPL. We found a striking 10-fold difference in hydrolysis rates across individuals when the particles were compared on a protein or a TG basis. While VLDL TG contents moderately correlated with hydrolysis rate, we noticed substantial variations in non-apoB proteins within these particles by MS. The ability of LPL to hydrolyze VLDL TGs did not correlate with apolipoprotein C-II content, but it was strongly inversely correlated with apolipoprotein E (APOE) and, to a lesser extent, apolipoprotein A-II. Addition of exogenous APOE inhibited LPL lipolysis in a dose-dependent manner. The APOE3 and (particularly) APOE4 isoforms were effective at limiting LPL hydrolysis, whereas APOE2 was not. We conclude that APOE on VLDL modulates LPL activity and could be a relevant factor in the pathogenesis of metabolic disease.

Highlights

IntroductionThe Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial found that administration of icosapent ethyl, a prescription omega-3 fatty acid, significantly reduced plasma TGs, CVD events, and CV-related death in patients with elevated TGs, known CVD disease, or were at a risk of developing CVD
Supplementary key words apolipoprotein(s) apolipoprotein E LPL lipoprotein metabolism lipoproteins VLDL chylomicrons metabolic disease TG-rich lipoproteins lipolysis
While several studies have investigated the impact of these proteins in various systems including engineered mouse models [24,25,26,27,28] and in vitro systems using synthetic emulsion substrates, we are aware of no studies that have determined the relative contributions of resident proteins on LPL activity in native VLDL particles isolated from humans

Summary

Introduction

The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial found that administration of icosapent ethyl, a prescription omega-3 fatty acid, significantly reduced plasma TGs, CVD events, and CV-related death in patients with elevated TGs, known CVD disease, or were at a risk of developing CVD. This occurred on top of existing statin therapy [7].

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