Critical Role of Neutral Cholesteryl Ester Hydrolase 1 in Cholesteryl Ester Hydrolysis in Murine Macrophages

Overview

Journal J Lipid Res

Publisher Elsevier

Specialty Biochemistry

Date 2014 May 29

PMID 24868095

Citations 19

Authors

Kent Sakai

Masaki Igarashi

Daisuke Yamamuro

Taichi Ohshiro

Shuichi Nagashima

Manabu Takahashi

Bolormaa Enkhtuvshin

Motohiro Sekiya

Hiroaki Okazaki

Jun-Ichi Osuga

Shun Ishibashi

Affiliations

Soon will be listed here.

Abstract

Hydrolysis of intracellular cholesteryl ester (CE) is the rate-limiting step in the efflux of cholesterol from macrophage foam cells. In mouse peritoneal macrophages (MPMs), this process is thought to involve several enzymes: hormone-sensitive lipase (Lipe), carboxylesterase 3 (Ces3), neutral CE hydrolase 1 (Nceh1). However, there is some disagreement over the relative contributions of these enzymes. To solve this problem, we first compared the abilities of several compounds to inhibit the hydrolysis of CE in cells overexpressing Lipe, Ces3, or Nceh1. Cells overexpressing Ces3 had negligible neutral CE hydrolase activity. We next examined the effects of these inhibitors on the hydrolysis of CE and subsequent cholesterol trafficking in MPMs. CE accumulation was increased by a selective inhibitor of Nceh1, paraoxon, and two nonselective inhibitors of Nceh1, (+)-AS115 and (-)-AS115, but not by two Lipe-selective inhibitors, orlistat and 76-0079. Paraoxon inhibited cholesterol efflux to apoA-I or HDL, while 76-0079 did not. These results suggest that Nceh1 plays a dominant role over Lipe in the hydrolysis of CE and subsequent cholesterol efflux in MPMs.

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