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.
Zhang
Jessie R
JR
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
Coleman
Trey
T
Langmade
S Joshua
SJ
Scherrer
David E
DE
Lane
Lindsay
L
Lanier
M Hunter
MH
Feng
Chu
C
Sands
Mark S
MS
Schaffer
Jean E
JE
Semenkovich
Clay F
CF
Ory
Daniel S
DS
D000821:Animal Feed; D000818:Animals; D001011:Aorta / Q000473:pathology; D050197:Atherosclerosis / Q000378:metabolism*; D001692:Biological Transport; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D006888:Hydroxycholesterols / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D000077296:Niemann-Pick C1 Protein; D018384:Oxidative Stress; D011506:Proteins / Q000235:genetics* / Q000502:physiology*; D013261:Sterols / Q000378:metabolism; D013997:Time Factors
D006888:Hydroxycholesterols; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D013261:Sterols; C076996:27-hydroxycholesterol; D002784:Cholesterol