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Niemann-Pick C1 protects against atherosclerosis in mice via regulation of macrophage intracellular cholesterol trafficking.
- Source :
-
Journal of Clinical Investigation . Jun2008, Vol. 118 Issue 6, p2281-2290. 10p. 3 Color Photographs, 1 Black and White Photograph, 1 Diagram, 1 Chart, 9 Graphs. - Publication Year :
- 2008
-
Abstract
- 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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *NIEMANN-Pick diseases
*GENE expression
*MACROPHAGES
*BLOOD cholesterol
*BLOOD lipoproteins
*CHOLESTEROL metabolism
*ANIMAL experimentation
*AORTA
*ATHEROSCLEROSIS
*BIOLOGICAL models
*BIOLOGICAL transport
*CHOLESTEROL
*COMPARATIVE studies
*FOOD
*RESEARCH methodology
*MEDICAL cooperation
*MICE
*PROTEINS
*RESEARCH
*STEROLS
*TIME
*OXIDATIVE stress
*EVALUATION research
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 118
- Issue :
- 6
- Database :
- Academic Search Index
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- 32546823
- Full Text :
- https://doi.org/10.1172/JCI32561