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Cardiovascular Research Advance Access first published online on January 8, 2009
This version [Corrected Proof] published online on January 26, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp007
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

NPC1 repression contributes to lipid accumulation in human macrophages exposed to environmental aryl hydrocarbons

Normand Podechard1, Eric Le Ferrec1, Amélie Rebillard1, Olivier Fardel1,2 and Valérie Lecureur1,*

1 Institut National de la Santé et de la Recherche Médicale (INSERM) U620, EA-SeRAIC, Team ‘Toxicity of polycyclic aromatic hydrocarbons’ (labellisée Ligue Nationale contre le Cancer), IFR140, Université de Rennes 1, Faculté des Sciences Pharmaceutiques et Biologiques, 2, Avenue du Pr L. Bernard, 35043 Rennes, France
2 Département HITC, Centre Hospitalier Universitaire, Rennes, France

* Corresponding author. Tel: +33 2 23 23 47 88; fax: +33 2 23 23 47 94. E-mail address: valerie.lecureur{at}univ-rennes1.fr

Aims: Aryl hydrocarbons (AHs), such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and benzo(a)pyrene (BP), are environmental contaminants promoting the development of atherosclerosis-related cardiovascular diseases. In order to identify molecular mechanisms involved in these effects, we have analysed AH-mediated regulation of the lipid trafficking Niemann–Pick type C1 protein (NPC1) and its contribution to AH-induced macrophage lipid accumulation.

Methods and results: Exposure of primary human macrophages to TCDD and BP decreased NPC1 mRNA expression in a time-dependent manner. NPC1 protein expression and NPC1-related acid sphingomyelinase activity were reduced in parallel. NPC1 was also similarly down-regulated in mice exposed to BP. Moreover, TCDD and BP were demonstrated to trigger lipid accumulation in human macrophages, as assessed by Oil Red O and Nile Red staining and cholesterol determination. Such lipid loading occurred at least partly in endosomal/lysosomal compartments as demonstrated by immunolabelling of lipid vesicles by the lysosome-associated membrane protein 1. These cellular phenotypic effects were found to be similar to those triggered by knock-down of NPC1 expression using siRNAs and were counteracted by NPC1 overexpression, thus supporting the contribution of NPC1 to AH-mediated lipid accumulation in macrophages. Finally, both NPC1 down-expression and lipid accumulation in response to TCDD were found to be abolished through knock-down of the AH receptor (AHR), a ligand-activated transcription factor mediating many effects of AHs.

Conclusion: Our data have shown that contaminants such as TCDD and BP repress NPC1 expression in macrophages in an AHR-dependent manner, which likely contributes to macrophage lipid accumulation caused by these environmental chemicals. Thus, NPC1 appears to be a new molecular target regulated by environmental AHs and putatively involved in their deleterious cardiovascular effects.

KEYWORDS Aryl hydrocarbon receptor; Lipid accumulation; Macrophage; Niemann–Pick type C1; TCDD

Time for primary review: 22 days


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