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

J Clin Invest. 2008 Jun;118(6):2281-90. doi: 10.1172/JCI32561.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animal Feed
  • Animals
  • Aorta / pathology
  • Atherosclerosis / metabolism*
  • Biological Transport
  • Cholesterol / blood
  • Cholesterol / metabolism*
  • Hydroxycholesterols / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Macrophages / metabolism*
  • Mice
  • Mice, Transgenic
  • Models, Biological
  • Oxidative Stress
  • Proteins / genetics*
  • Proteins / physiology*
  • Sterols / metabolism
  • Time Factors

Substances

  • Hydroxycholesterols
  • Intracellular Signaling Peptides and Proteins
  • Npc1 protein, mouse
  • Proteins
  • Sterols
  • 27-hydroxycholesterol
  • Cholesterol