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Deficiency of adipose differentiation-related protein impairs foam cell formation and protects against atherosclerosis.

ABSTRACT: Foam cells are a hallmark of atherosclerosis. However, it is unclear whether foam cell formation per se protects against atherosclerosis or fuels it. In this study, we investigated the role of adipose differentiation-related protein (ADFP), a major lipid droplet protein (LDP), in the regulation of foam cell formation and atherosclerosis. We show that ADFP expression facilitates foam cell formation induced by modified lipoproteins in mouse macrophages in vitro. We show further that Adfp gene inactivation in apolipoprotein E-deficient (ApoE(-/-)) mice reduces the number of lipid droplets in foam cells in atherosclerotic lesions and protects the mice against atherosclerosis. Moreover, transplantation of ADFP-null bone marrow-derived cells effectively attenuated atherosclerosis in ApoE(-/-) mice. Deficiency of ADFP did not cause a detectable compensatory increase in the other PAT domain proteins in macrophages in vitro or in vivo. Mechanistically, ADFP enables the macrophage to maintain its lipid content by hindering lipid efflux. We detected no significant difference in lesion composition or in multiple parameters of inflammation in macrophages or in their phagocytic activity between mice with and without ADFP. In conclusion, Adfp inactivation in ApoE(-/-) background protects against atherosclerosis and appears to be a relatively pure model of impaired foam cell formation.

SUBMITTER: Paul A

PROVIDER: S-EPMC2773502 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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Deficiency of adipose differentiation-related protein impairs foam cell formation and protects against atherosclerosis.

Paul Antoni A Chang Benny Hung-Junn BH Li Lan L Yechoor Vijay K VK Chan Lawrence L

Circulation research 20080515 12

Foam cells are a hallmark of atherosclerosis. However, it is unclear whether foam cell formation per se protects against atherosclerosis or fuels it. In this study, we investigated the role of adipose differentiation-related protein (ADFP), a major lipid droplet protein (LDP), in the regulation of foam cell formation and atherosclerosis. We show that ADFP expression facilitates foam cell formation induced by modified lipoproteins in mouse macrophages in vitro. We show further that Adfp gene inac ...[more]

PMID: 18483409

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Project description:Objective- Inflammatory stimuli enhance the progression of atherosclerotic disease. Inflammation also increases the expression of hepcidin, a hormonal regulator of iron homeostasis, which decreases intestinal iron absorption, reduces serum iron levels and traps iron within macrophages. The role of macrophage iron in the development of atherosclerosis remains incompletely understood. The objective of this study was to investigate the effects of hepcidin deficiency and decreased macrophage iron on the development of atherosclerosis. Approach and Results- Hepcidin- and LDL (low-density lipoprotein) receptor-deficient ( Hamp-/-/ Ldlr-/-) mice and Hamp+/+/ Ldlr-/- control mice were fed a high-fat diet for 21 weeks. Compared with control mice, Hamp-/-/ Ldlr-/- mice had decreased aortic macrophage activity and atherosclerosis. Because hepcidin deficiency is associated with both increased serum iron and decreased macrophage iron, the possibility that increased serum iron was responsible for decreased atherosclerosis in Hamp-/-/ Ldlr-/- mice was considered. Hamp+/+/ Ldlr-/- mice were treated with iron dextran so as to produce a 2-fold increase in serum iron. Increased serum iron did not decrease atherosclerosis in Hamp+/+/ Ldlr-/- mice. Aortic macrophages from Hamp-/-/ Ldlr-/- mice had less labile free iron and exhibited a reduced proinflammatory (M1) phenotype compared with macrophages from Hamp+/+/ Ldlr-/- mice. THP1 human macrophages treated with an iron chelator were used to model hepcidin deficiency in vitro. Treatment with an iron chelator reduced LPS (lipopolysaccharide)-induced M1 phenotypic expression and decreased uptake of oxidized LDL. Conclusions- In summary, in a hyperlipidemic mouse model, hepcidin deficiency was associated with decreased macrophage iron, a reduced aortic macrophage inflammatory phenotype and protection from atherosclerosis. The results indicate that decreasing hepcidin activity, with the resulting decrease in macrophage iron, may prove to be a novel strategy for the treatment of atherosclerosis.

Dataset Information

Deficiency of adipose differentiation-related protein impairs foam cell formation and protects against atherosclerosis.

Publications

Deficiency of adipose differentiation-related protein impairs foam cell formation and protects against atherosclerosis.

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