OxLDL induces macrophage γ-GCS-HS protein expression: a role for oxLDL-associated lipid hydroperoxide in GSH synthesis
Oxidized LDL (oxLDL) produced a rapid depletion of intracellular glutathione (GSH) followed by an adaptive increase in J774 A.1 macrophages. OxLDL also induced a transient increase in the levels of γ-glutamylcysteine synthetase heavy subunit (γ-GCS-HS), representing the catalytic subunit of the rate...
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doaj-9e2c134e9f6e4123a75f90762bee67c02021-04-27T04:40:26ZengElsevierJournal of Lipid Research0022-22752001-05-01425813823OxLDL induces macrophage γ-GCS-HS protein expression: a role for oxLDL-associated lipid hydroperoxide in GSH synthesisLijiang Shen0Alex Sevanian1Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90033Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90033; To whom correspondence should be addressed. e-mail:Oxidized LDL (oxLDL) produced a rapid depletion of intracellular glutathione (GSH) followed by an adaptive increase in J774 A.1 macrophages. OxLDL also induced a transient increase in the levels of γ-glutamylcysteine synthetase heavy subunit (γ-GCS-HS), representing the catalytic subunit of the rate-limiting enzyme for de novo GSH synthesis. The induction took place within 3 h, with maximum levels observed by 10 h of treatment. Pretreatment of oxLDL with ebselen inhibited GSH depletion and attenuated the γ-GCS-HS induction. OxLDL-associated lipid hydroperoxides and their decomposition product aldehydes are two major components thought to account for GSH depletion in macrophages. Ebselen pretreatment had only a minor effect on malondialdehyde levels, whereas peroxide content was essentially abolished, suggesting that oxLDL-associated hydroperoxides may mediate both GSH depletion and γ-GCS-HS induction. Acetylated LDL (AcLDL) also caused a moderate induction of γ-GCS-HS protein along with a 30% transient increase in GSH by 3–6 h, suggesting a minor involvement of scavenger receptor-mediated signaling of GSH synthesis. However, the level of γ-GCS induction by AcLDL was insufficient to cause a sustained increase in GSH. Macrophages with higher glutathione peroxidase (GPx) activity experienced a more rapid and extensive depletion of GSH when treated with oxLDL under similar conditions, along with greater resistance to oxLDL- or peroxide-induced cytotoxicity.We conclude that oxLDL-associated peroxides are primarily responsible for GSH depletion, creating an oxidizing environment required for γ-GCS induction and compensatory GSH synthesis. This is facilitated in cells expressing high GPx activity through a rapid depletion of GSH in the face of a peroxide challenge.http://www.sciencedirect.com/science/article/pii/S0022227520316448oxidized low density lipoproteinγ-glutamylcysteine synthetasereactive oxygen species |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lijiang Shen Alex Sevanian |
spellingShingle |
Lijiang Shen Alex Sevanian OxLDL induces macrophage γ-GCS-HS protein expression: a role for oxLDL-associated lipid hydroperoxide in GSH synthesis Journal of Lipid Research oxidized low density lipoprotein γ-glutamylcysteine synthetase reactive oxygen species |
author_facet |
Lijiang Shen Alex Sevanian |
author_sort |
Lijiang Shen |
title |
OxLDL induces macrophage γ-GCS-HS protein expression: a role for oxLDL-associated lipid hydroperoxide in GSH synthesis |
title_short |
OxLDL induces macrophage γ-GCS-HS protein expression: a role for oxLDL-associated lipid hydroperoxide in GSH synthesis |
title_full |
OxLDL induces macrophage γ-GCS-HS protein expression: a role for oxLDL-associated lipid hydroperoxide in GSH synthesis |
title_fullStr |
OxLDL induces macrophage γ-GCS-HS protein expression: a role for oxLDL-associated lipid hydroperoxide in GSH synthesis |
title_full_unstemmed |
OxLDL induces macrophage γ-GCS-HS protein expression: a role for oxLDL-associated lipid hydroperoxide in GSH synthesis |
title_sort |
oxldl induces macrophage γ-gcs-hs protein expression: a role for oxldl-associated lipid hydroperoxide in gsh synthesis |
publisher |
Elsevier |
series |
Journal of Lipid Research |
issn |
0022-2275 |
publishDate |
2001-05-01 |
description |
Oxidized LDL (oxLDL) produced a rapid depletion of intracellular glutathione (GSH) followed by an adaptive increase in J774 A.1 macrophages. OxLDL also induced a transient increase in the levels of γ-glutamylcysteine synthetase heavy subunit (γ-GCS-HS), representing the catalytic subunit of the rate-limiting enzyme for de novo GSH synthesis. The induction took place within 3 h, with maximum levels observed by 10 h of treatment. Pretreatment of oxLDL with ebselen inhibited GSH depletion and attenuated the γ-GCS-HS induction. OxLDL-associated lipid hydroperoxides and their decomposition product aldehydes are two major components thought to account for GSH depletion in macrophages. Ebselen pretreatment had only a minor effect on malondialdehyde levels, whereas peroxide content was essentially abolished, suggesting that oxLDL-associated hydroperoxides may mediate both GSH depletion and γ-GCS-HS induction. Acetylated LDL (AcLDL) also caused a moderate induction of γ-GCS-HS protein along with a 30% transient increase in GSH by 3–6 h, suggesting a minor involvement of scavenger receptor-mediated signaling of GSH synthesis. However, the level of γ-GCS induction by AcLDL was insufficient to cause a sustained increase in GSH. Macrophages with higher glutathione peroxidase (GPx) activity experienced a more rapid and extensive depletion of GSH when treated with oxLDL under similar conditions, along with greater resistance to oxLDL- or peroxide-induced cytotoxicity.We conclude that oxLDL-associated peroxides are primarily responsible for GSH depletion, creating an oxidizing environment required for γ-GCS induction and compensatory GSH synthesis. This is facilitated in cells expressing high GPx activity through a rapid depletion of GSH in the face of a peroxide challenge. |
topic |
oxidized low density lipoprotein γ-glutamylcysteine synthetase reactive oxygen species |
url |
http://www.sciencedirect.com/science/article/pii/S0022227520316448 |
work_keys_str_mv |
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