The Role of Neutral Cholesterol Ester Hydrolysis in Macrophage Foam Cells

Sekiya, Motohiro; Osuga, Jun-ichi; Igarashi, Masaki; Okazaki, Hiroaki; Ishibashi, Shun

doi:10.5551/jat.7013

Cited by 61 publications

(36 citation statements)

References 48 publications

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“…19 HSL is a cytoplasmic enzyme that translocates to LDs on activation. 20 Macrophage-specific HSL and apolipoprotein A-IV transgenic expression in mice fed an atherogenic diet reduces the size of aortic lesions, 21 similar to what is observed on increased macrophage CEH activity.…”

Section: Neutral Lipolysismentioning

confidence: 61%

“…24 Although the mechanism of this association is unclear, this interaction possibly arises from a close association of LDs with the ER or, alternatively, occurs via presently uncharacterized associating molecules. 20 Together, knock down of Nceh1 and HSL in macrophages nearly completely abolishes all CE hydrolysis in cell-free assays. 23 In vivo, macrophage-specific ablation of Nceh1 increases atherosclerosis plaque development, as does macrophage-specific HSL ablation, and together a compound lack of macrophage Nceh1 and HSL has an additive effect on promoting atherogenesis.…”

Section: Neutral Lipolysismentioning

confidence: 99%

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Regulation of Lipid Droplet Cholesterol Efflux From Macrophage Foam Cells

Ouimet

Marcel

2012

ATVB

190

139

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Abstract-Cholesterol efflux from macrophages is the first and potentially most important step in reverse cholesterol transport, a process especially relevant to atherosclerosis and to the regression of atherosclerotic plaques. Increasingly, lipid droplet (LD) cholesteryl ester (CE) hydrolysis is being recognized as a rate-limiting step in cholesterol efflux. The traditional view on macrophage CE hydrolysis is that this pathway is entirely dependent on the action of neutral hydrolases, and numerous candidate CE hydrolases have been proposed to play a role in lipid hydrolysis in macrophages and atherogenesis. Although the exact identity of macrophage-specific CE hydrolases remains to be clarified, a common point to all of these studies is that enhancing LD-associated CE hydrolysis increases cholesterol efflux and is antiatherogenic. Understanding how cholesterol is mobilized from LDs offers new steps for modulating cholesterol efflux, and recently a role for autophagy and lysosomal acid lipase in macrophage lipolysis has emerged. Autophagy and lysosomal acid lipase thus represent novel therapeutic targets to enhance macrophage reverse cholesterol transport. This review discusses our current understanding of the relationship between macrophage LDs and atherosclerosis and presents recent insights into the mechanisms for LD CE hydrolysis in macrophage foam cells. (Arterioscler Thromb Vasc Biol. 2012;32:575-581.)

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Section: Neutral Lipolysismentioning

confidence: 61%

Section: Neutral Lipolysismentioning

confidence: 99%

Regulation of Lipid Droplet Cholesterol Efflux From Macrophage Foam Cells

Ouimet

Marcel

2012

ATVB

190

139

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“…In the present study, OxLDL promoted the uptake of cholesterol and its esterification in THP1 macrophages through increased gene expression of CD36 and SRA1, the main pathways of cholesterol uptake in macrophages [33], and of ACAT, which re-esterifies cholesterol inside macrophages [34]. Cortisol inhibited the expression of CD36, SRA1 and ACAT, thus limiting the influx of cholesterol.…”

Section: Discussionmentioning

confidence: 95%

Decreased OxLDL uptake and cholesterol efflux in THP1 cells elicited by cortisol and by cortisone through 11β-hydroxysteroid dehydrogenase type 1

et al. 2016

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“…In RA, these CD1c+mDC induce proliferation and cytokine secretion of autologous CD4+ T cells (27). Furthermore, CD1c is strongly induced in foam cell macrophages (FCM), which are characterized by their strong intracellular accumulation of CE (28,29). FCM are typically seen in the inflammatory lesions of atherosclerosis but are also present in other chronic inflammatory and infectious conditions, including, for example, tuberculosis (30).…”

Section: Discussionmentioning

confidence: 99%

Cholesteryl esters stabilize human CD1c conformations for recognition by self-reactive T cells

Mansour

Tocheva

Cave-Ayland

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cluster of differentiation 1c (CD1c)-dependent self-reactive T cells are abundant in human blood, but self-antigens presented by CD1c to the T-cell receptors of these cells are poorly understood. Here we present a crystal structure of CD1c determined at 2.4 Å revealing an extended ligand binding potential of the antigen groove and a substantially different conformation compared with known CD1c structures. Computational simulations exploring different occupancy states of the groove reenacted these different CD1c conformations and suggested cholesteryl esters (CE) and acylated steryl glycosides (ASG) as new ligand classes for CD1c. Confirming this, we show that binding of CE and ASG to CD1c enables the binding of human CD1c self-reactive T-cell receptors. Hence, human CD1c adopts different conformations dependent on ligand occupancy of its groove, with CE and ASG stabilizing CD1c conformations that provide a footprint for binding of CD1c self-reactive T-cell receptors.CD1 | lipid antigen | antigen presentation | T cell | cholesteryl ester C luster of differentiation 1 (CD1) proteins are a family of MHC class I-like glycoproteins that present lipid antigens to T cells. CD1 restricted T cells are abundant in humans and play important roles in host defense and immune regulation. Human CD1 proteins comprise five CD1 isoforms, CD1a, CD1b, CD1c, CD1d, and CD1e, which exhibit different intracellular trafficking behaviors and ligand binding preferences (1). Structurally, the main differences between these CD1 isoforms lie in the architecture of their lipophilic ligand binding grooves. Whereas all CD1 isoforms share a highly conserved A′ channel (or pocket) for binding C18-C26 acyl chains, specialization is provided by further connecting channels (2-7). In CD1a, the A′ channel is "fused" to a wide and shallow F′ channel, enabling binding of lipopeptides such as mycobacterial didehydroxymycobactin (DDM) (8). CD1b features a unique T′ tunnel that connects A′ and F′, thereby forming a "superchannel" for accommodating very long acyl chains (e.g., mycobacterial mycolates) (2, 4). CD1d, the only isoform also conserved in rodents, exhibits a twobranched ligand binding groove with two linear channels A′ and F′ connected near the main portal into the groove, known as the F′ portal. A similar two-branched arrangement of A′ and F′ is seen in CD1e, the only CD1 isoform not expressed on the cell surface. Compared with CD1d, CD1a, and CD1b, the portal into the groove in CD1e is widely exposed, consistent with its known role in lipid transfer processes inside lysosomes (6).CD1c presents foreign-(9, 10) as well as self-lipid antigens to T cells (11). Two recent crystal structures of human CD1c revealed a two-branched design similar to that of CD1d and CD1e, with two channels A′ and F′ connecting near the groove portal. In these structures, a mycobacterial phosphomycoketide (PM) or mannosyl-β1-phosphomycoketide (MPM) occupied the A′ channel, whereas an undefined short ligand was present in the F′ channel (7, 12). The spatial arrangement of...

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The Role of Neutral Cholesterol Ester Hydrolysis in Macrophage Foam Cells

Cited by 61 publications

References 48 publications

Regulation of Lipid Droplet Cholesterol Efflux From Macrophage Foam Cells

Regulation of Lipid Droplet Cholesterol Efflux From Macrophage Foam Cells

Decreased OxLDL uptake and cholesterol efflux in THP1 cells elicited by cortisol and by cortisone through 11β-hydroxysteroid dehydrogenase type 1

Cholesteryl esters stabilize human CD1c conformations for recognition by self-reactive T cells

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