Niemann-Pick C1 protects against atherosclerosis in mice via regulation of macrophage intracellular cholesterol trafficking
Niemann-Pick C1 (NPC1) is a key participant in cellular cholesterol trafficking. Loss of NPC1 function leads to defective suppression of SREBP-dependent gene expression and failure to appropriately activate liver X receptor-mediated (LXR-mediated) pathways, ultimately resulting in intracellular cholesterol accumulation. To determine whether NPC1 contributes to regulation of macrophage sterol homeostasis in vivo, we examined the effect of NPC1 deletion in BM-derived cells on atherosclerotic lesion development in the Ldlr-/- mouse model of atherosclerosis. High-fat diet-fed chimeric Npc1-/- mice reconstituted with Ldlr-/-Npc1-/- macrophages exhibited accelerated atherosclerosis despite lower serum cholesterol compared with mice reconstituted with wild-type macrophages. The discordance between the low serum lipoprotein levels and the presence of aortic atherosclerosis suggested that intrinsic alterations in macrophage sterol metabolism in the chimeric Npc1-/- mice played a greater role in atherosclerotic lesion formation than did serum lipoprotein levels. Macrophages from chimeric Npc1-/- mice showed decreased synthesis of 27-hydroxycholesterol (27-HC), an endogenous LXR ligand; decreased expression of LXR-regulated cholesterol transporters; and impaired cholesterol efflux. Lower 27-HC levels were associated with elevated cholesterol oxidation products in macrophages and plasma of chimeric Npc1-/- mice and with increased oxidative stress. Our results demonstrate that NPC1 serves an atheroprotective role in mice through regulation of LXR-dependent cholesterol efflux and mitigation of cholesterol-induced oxidative stress in macrophages.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2008 |
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| Erschienen: |
2008 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:118 |
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| Enthalten in: |
The Journal of clinical investigation - 118(2008), 6 vom: 23. Juni, Seite 2281-90 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhang, Jessie R [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 10.07.2008 Date Revised 03.12.2021 published: Print Citation Status MEDLINE |
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| doi: |
10.1172/JCI32561 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM179604376 |
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| 100 | 1 | |a Zhang, Jessie R |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Niemann-Pick C1 protects against atherosclerosis in mice via regulation of macrophage intracellular cholesterol trafficking |
| 264 | 1 | |c 2008 | |
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| 500 | |a Date Revised 03.12.2021 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Niemann-Pick C1 (NPC1) is a key participant in cellular cholesterol trafficking. Loss of NPC1 function leads to defective suppression of SREBP-dependent gene expression and failure to appropriately activate liver X receptor-mediated (LXR-mediated) pathways, ultimately resulting in intracellular cholesterol accumulation. To determine whether NPC1 contributes to regulation of macrophage sterol homeostasis in vivo, we examined the effect of NPC1 deletion in BM-derived cells on atherosclerotic lesion development in the Ldlr-/- mouse model of atherosclerosis. High-fat diet-fed chimeric Npc1-/- mice reconstituted with Ldlr-/-Npc1-/- macrophages exhibited accelerated atherosclerosis despite lower serum cholesterol compared with mice reconstituted with wild-type macrophages. The discordance between the low serum lipoprotein levels and the presence of aortic atherosclerosis suggested that intrinsic alterations in macrophage sterol metabolism in the chimeric Npc1-/- mice played a greater role in atherosclerotic lesion formation than did serum lipoprotein levels. Macrophages from chimeric Npc1-/- mice showed decreased synthesis of 27-hydroxycholesterol (27-HC), an endogenous LXR ligand; decreased expression of LXR-regulated cholesterol transporters; and impaired cholesterol efflux. Lower 27-HC levels were associated with elevated cholesterol oxidation products in macrophages and plasma of chimeric Npc1-/- mice and with increased oxidative stress. Our results demonstrate that NPC1 serves an atheroprotective role in mice through regulation of LXR-dependent cholesterol efflux and mitigation of cholesterol-induced oxidative stress in macrophages | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Hydroxycholesterols |2 NLM | |
| 650 | 7 | |a Intracellular Signaling Peptides and Proteins |2 NLM | |
| 650 | 7 | |a Niemann-Pick C1 Protein |2 NLM | |
| 650 | 7 | |a Npc1 protein, mouse |2 NLM | |
| 650 | 7 | |a Proteins |2 NLM | |
| 650 | 7 | |a Sterols |2 NLM | |
| 650 | 7 | |a 27-hydroxycholesterol |2 NLM | |
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| 650 | 7 | |a Cholesterol |2 NLM | |
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| 700 | 1 | |a Coleman, Trey |e verfasserin |4 aut | |
| 700 | 1 | |a Langmade, S Joshua |e verfasserin |4 aut | |
| 700 | 1 | |a Scherrer, David E |e verfasserin |4 aut | |
| 700 | 1 | |a Lane, Lindsay |e verfasserin |4 aut | |
| 700 | 1 | |a Lanier, M Hunter |e verfasserin |4 aut | |
| 700 | 1 | |a Feng, Chu |e verfasserin |4 aut | |
| 700 | 1 | |a Sands, Mark S |e verfasserin |4 aut | |
| 700 | 1 | |a Schaffer, Jean E |e verfasserin |4 aut | |
| 700 | 1 | |a Semenkovich, Clay F |e verfasserin |4 aut | |
| 700 | 1 | |a Ory, Daniel S |e verfasserin |4 aut | |
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| 773 | 1 | 8 | |g volume:118 |g year:2008 |g number:6 |g day:23 |g month:06 |g pages:2281-90 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1172/JCI32561 |3 Volltext |
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