Lipoprotein size is a main determinant for the rate of hydrolysis by exogenous LPL in human plasma

Oleg Kovrov,Fredrik Landfors,Valeria Saar-Kovrov,Ulf Näslund,Gunilla Olivecrona

doi:10.1016/j.jlr.2021.100144

Oleg Kovrov, Fredrik Landfors + Show 3 more

Open Access

https://doi.org/10.1016/j.jlr.2021.100144

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Abstract

LPL is a key player in plasma triglyceride metabolism. Consequently, LPL is regulated by several proteins during synthesis, folding, secretion, and transport to its site of action at the luminal side of capillaries, as well as during the catalytic reaction. Some proteins are well known, whereas others have been identified but are still not fully understood. We set out to study the effects of the natural variations in the plasma levels of all known LPL regulators on the activity of purified LPL added to samples of fasted plasma taken from 117 individuals. The enzymatic activity was measured at 25°C using isothermal titration calorimetry. This method allows quantification of the ability of an added fixed amount of exogenous LPL to hydrolyze triglyceride-rich lipoproteins in plasma samples by measuring the heat produced. Our results indicate that, under the conditions used, the normal variation in the endogenous levels of apolipoprotein C1, C2, and C3 or the levels of angiopoietin-like proteins 3, 4, and 8 in the fasted plasma samples had no significant effect on the recorded activity of the added LPL. Instead, the key determinant for the LPL activity was a lipid signature strongly correlated to the average size of the VLDL particles. The signature involved not only several lipoprotein and plasma lipid parameters but also apolipoprotein A5 levels. While the measurements cannot fully represent the action of LPL when attached to the capillary wall, our study provides knowledge on the interindividual variation of LPL lipolysis rates in human plasma.

Highlights

Cardiovascular disease (CVD) is one of the main causes of death and morbidity in modern society [1]
Under the conditions used, the normal variation in the endogenous levels of apolipoprotein C1, C2 and C3, or the levels of angiopoietin-like proteins 3, 4, and 8 in the fasted plasma samples had no significant effect on the recorded activity of the added lipoprotein lipase (LPL)
Other important control proteins for LPL include the apolipoproteins (Apos), that are found on the surface of triglyceride-rich lipoproteins (TRL), and angiopoietin-like proteins (ANGPTL) which regulate the amount of active LPL in the tissues in response to metabolic and hormonal signals [8]

Summary

Introduction

Cardiovascular disease (CVD) is one of the main causes of death and morbidity in modern society [1]. Recent genetic evidence suggests that plasma triglycerides (TG), triglyceride-rich lipoproteins (TRL) and TRL remnants play major roles in the progression of CVD [2]. TG levels in the blood are to a large extent regulated by the action of lipoprotein lipase (LPL) [3]. A major part of the LPL regulation occurs post-translationally: either in the parenchymal cells of muscle and adipose tissue; during the secretion and transendothelial transport of the enzyme by the glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) to the site of action on the capillary endothelium; or, during the action of LPL on the TRL. Other important control proteins for LPL include the apolipoproteins (Apos), that are found on the surface of TRL, and angiopoietin-like proteins (ANGPTL) which regulate the amount of active LPL in the tissues in response to metabolic and hormonal signals [8]

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