ABCA12 Regulates ABCA1-Dependent Cholesterol Efflux from Macrophages and the Development of Atherosclerosis

作者：Fu Ying; Mukhamedova Nigora; Ip Sally; D' Souza Wilissa; Henley Katya J; DiTommaso Tia; Kesani Rajitha; Ditiatkovski Michael; Jones Lynelle; Lane Rachael M; Jennings Garry; Smyth Ian M; Kile Benjamin T; Sviridov Dmitri^*

来源：Cell Metabolism, 2013, 18(2): 225-238.

DOI：10.1016/j.cmet.2013.07.003

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 Lxr beta. Overexpression of Lxr beta reversed the effects. Mechanistically, Abca12 deficiency did not affect expression of genes involved in cholesterol metabolism. Instead, a physical association between Abca1, Abca12, and Lxr beta proteins was established. Abca12 deficiency enhanced interaction between Abca1 and Lxr beta 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 LXR beta-dependent posttranscriptional mechanism.

• 出版日期2013-8-6
• 单位河北医科大学