Aryl hydrocarbons cause lipid accumulation in macrophages, contribute to atherosclerosis
Kofi
NPC1 repression contributes to lipid accumulation in human macrophages
exposed to environmental aryl hydrocarbons.
Podechard N, Le Ferrec E, Rebillard A, Fardel O, Lecureur V.
Institut National de la Sante et de la Recherche Medicale U620, IFR140,
Universite de Rennes 1, Faculte des Sciences Pharmaceutiques et
Biologiques, 2, Avenue du Pr L. Bernard, 35043 Rennes, France.
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.
Publication Types:
* Research Support, Non-U.S. Gov't
PMID: 19131362
n-3 fatty acids decrease gene expression of NPC1L1 in hamster
intestines, perhaps through activation of PPARdelta which interferes
with cholesterol trafficking to the endoplasmic reticulum; this occurs
independent of changes to ABCG8 [PMID 17114806]