ABCA12 Regulates ABCA1-Dependent Cholesterol Efflux from Macrophages and the Development of Atherosclerosis
Copyright policy )ABCA12 Regulates ABCA1-Dependent Cholesterol Efflux from Macrophages and the Development of Atherosclerosis
ABCA12 is involved in the transport of ceramides in skin, but it may play a wider role in lipid metabolism. We show that, in Abca12-deficient macrophages, cholesterol efflux failed to respond to activation with LXR agonists. Abca12 deficiency caused a reduction in the abundance of Abca1, Abcg1, and Lxrβ. Overexpression of Lxrβ reversed the effects. Mechanistically, Abca12 deficiency did not affect expression of genes involved in cholesterol metabolism. Instead, a physical association between Abca1, Abca12, and Lxrβ proteins was established. Abca12 deficiency enhanced interaction between Abca1 and Lxrβ and the degradation of Abca1. Overexpression of ABCA12 in HeLa-ABCA1 cells increased the abundance and stability of ABCA1. Abca12 deficiency caused an accumulation of cholesterol in macrophages and the formation of foam cells, impaired reverse cholesterol transport in vivo, and increased the development of atherosclerosis in irradiated Apoe(-/-) mice reconstituted with Apoe(-/-)Abca12(-/-) bone marrow. Thus, ABCA12 regulates the cellular cholesterol metabolism via an LXRβ-dependent posttranscriptional mechanism.
- Monash University Australia
- University of Melbourne Australia
- Monash University, Clayton campus Australia
- Walter and Eliza Hall Institute of Medical Research Australia
- Baker IDI Heart and Diabetes Institute Australia
Physiology, Lipoproteins, Mice, Transgenic, Cell Line, Mice, 616, Animals, Humans, Molecular Biology, ATP Binding Cassette Transporter, Subfamily G, Member 1, Liver X Receptors, Macrophages, Biological Transport, Cell Biology, Atherosclerosis, Lipid Metabolism, Orphan Nuclear Receptors, Mice, Inbred C57BL, Cholesterol, ATP-Binding Cassette Transporters, ATP Binding Cassette Transporter 1, Foam Cells, HeLa Cells
Physiology, Lipoproteins, Mice, Transgenic, Cell Line, Mice, 616, Animals, Humans, Molecular Biology, ATP Binding Cassette Transporter, Subfamily G, Member 1, Liver X Receptors, Macrophages, Biological Transport, Cell Biology, Atherosclerosis, Lipid Metabolism, Orphan Nuclear Receptors, Mice, Inbred C57BL, Cholesterol, ATP-Binding Cassette Transporters, ATP Binding Cassette Transporter 1, Foam Cells, HeLa Cells
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