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PMID: 18483620 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Niemann-Pick C1 protects against atherosclerosis in mice via regulation of macrophage intracellular cholesterol trafficking.

The Journal of clinical investigation ·Vol. 118 ·No. 6 ·2008-06-00 ·Pages 2281-90

Zhang JR, Coleman T, Langmade SJ, Scherrer DE, Lane L, Lanier MH, Feng C, Sands MS, Schaffer JE, Semenkovich CF, Ory DS

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.

MeSH Terms
Animal Feed Animals Aorta/pathology Atherosclerosis/metabolism Biological Transport Cholesterol/blood,metabolism Hydroxycholesterols/metabolism Intracellular Signaling Peptides and Proteins Macrophages/metabolism Mice Mice, Transgenic Models, Biological Niemann-Pick C1 Protein Oxidative Stress Proteins/genetics,physiology Sterols/metabolism Time Factors
Chemicals
Hydroxycholesterols Intracellular Signaling Peptides and Proteins Niemann-Pick C1 Protein Npc1 protein, mouse Proteins Sterols 27-hydroxycholesterol Cholesterol
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Zhang Jessie R
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
Coleman Trey
Langmade S Joshua
Scherrer David E
Lane Lindsay
Lanier M Hunter
Feng Chu
Sands Mark S
Schaffer Jean E
Semenkovich Clay F
Ory Daniel S
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI32561
Published
2008-06-00
Pages
2281-90
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC2381744
Subset
IM
Grants
NINDS NIH HHS · R01 NS043205 · United States
NIDDK NIH HHS · R01 DK064989 · United States
NIDDK NIH HHS · DK57586 · United States
NIDDK NIH HHS · P30 DK56341 · United States
NIDDK NIH HHS · R01 DK057586 · United States
NCRR NIH HHS · P20 RR020643 · United States
NIDDK NIH HHS · P30 DK52574 · United States
NIDDK NIH HHS · P30 DK052574 · United States
NHLBI NIH HHS · P50 HL083762 · United States
NCRR NIH HHS · RR020643 · United States
NIDDK NIH HHS · P30 DK056341-08 · United States
NIDDK NIH HHS · DK076729 · United States
NIDDK NIH HHS · P30 DK056341 · United States
NIDDK NIH HHS · P30 DK056341-07 · United States
NHLBI NIH HHS · HL067773 · United States
NIDDK NIH HHS · R01 DK076729 · United States
NICHD NIH HHS · R01 HD055461 · United States
NIDDK NIH HHS · R56 DK064989 · United States
NIDDK NIH HHS · P60 DK020579 · United States
NIDDK NIH HHS · DK064989 · United States
NHLBI NIH HHS · R01 HL067773 · United States
External Links
PubMed source DOI: 10.1172/JCI32561 PMC Full Text View journal details
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