Endothelial lipase is less effective at influencing HDL metabolism in vivo in mice expressing apoA-II

Uli C Broedl,John S Millar,Weijun Jin,Daniel J Rader,Ilia V Fuki

doi:10.1194/jlr.m600036-jlr200

Uli C Broedl, John S Millar + Show 3 more

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https://doi.org/10.1194/jlr.m600036-jlr200

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Abstract

Endothelial lipase (EL) plays an important physiological role in modulating HDL metabolism. Data suggest that plasma contains an inhibitor of EL, and previous studies have suggested that apolipoprotein A-II (apoA-II) inhibits the activity of several enzymes involved in HDL metabolism. Therefore, we hypothesized that apoA-II may reduce the ability of EL to influence HDL metabolism. To test this hypothesis, we determined the effect of EL expression on plasma phospholipase activity and HDL metabolism in human apoA-I and human apoA-I/A-II transgenic mice. Expression of EL in vivo resulted in lower plasma phospholipase activity and significantly less reduction of HDL-cholesterol, phospholipid, and apoA-I levels in apoA-I/A-II double transgenic mice compared with apoA-I single transgenic mice. We conclude that the presence of apoA-II on HDL particles inhibits the ability of EL to influence the metabolism of HDL in vivo.

Highlights

Endothelial lipase (EL) plays an important physiological role in modulating HDL metabolism
To test the hypothesis that apolipoprotein A-II (apoA-II) inhibits the effect of EL on HDL metabolism in vivo, we injected human apolipoprotein A-I (apoA-I) and human apoA-I/A-II transgenic mice with a relatively low dose of 3 3 1010 particles of adenoviral vector encoding human endothelial lipase (AdhEL)
Expression of EL resulted in significantly lower postheparin phospholipase activity in apoA-I/A-II compared with apoA-I transgenic mice on day 7 after virus injection (Fig. 1B)

Summary

Introduction

Endothelial lipase (EL) plays an important physiological role in modulating HDL metabolism. We hypothesized that apoA-II may reduce the ability of EL to influence HDL metabolism To test this hypothesis, we determined the effect of EL expression on plasma phospholipase activity and HDL metabolism in human apoA-I and human apoA-I/A-II transgenic mice. ApoA-II has a higher lipid affinity than apoA-I and is able to displace apoA-I from lipoprotein particles [9, 10] Both apolipoproteins directly affect HDL remodeling catalyzed by the interfacially active proteins found in the plasma. Based on the ability of apoA-II to inhibit other enzymes and transfer proteins involved with HDL metabolism, we hypothesized that apoA-II may be one of the inhibitory factors modulating EL activity To test this hypothesis, human apoA-I and apoA-I/A-II double transgenic mice were injected with low doses of an adenoviral vector encoding human endothelial lipase (AdhEL). ApoA-II expression substantially inhibits the effect of EL on HDL metabolism in vivo

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