ABCA12 regulates ABCA1-dependent cholesterol efflux from macrophages and the development of atherosclerosis

Ying Fu, Nigora Mukhamedova, Sally Chi Ieng Ip, Wilissa Rose D'Souza, Katya J Henley, Tia Marie Ditommaso, Rajitha Kesani, Michael Ditiatkovski, Lynelle Karyn Jones, Rachael M Lane, Garry L R Jennings, Ian Macleod Smyth, Benjamin Kile, Dimitri Sviridov

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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 Lxrbeta. Overexpression of Lxrbeta reversed the effects. Mechanistically, Abca12 deficiency did not affect expression of genes involved in cholesterol metabolism. Instead, a physical association between Abca1, Abca12, and Lxrbeta proteins was established. Abca12 deficiency enhanced interaction between Abca1 and Lxrbeta 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 LXRbeta-dependent posttranscriptional mechanism.
Original languageEnglish
Pages (from-to)225-238
Number of pages14
JournalCell Metabolism
Volume18
Issue number2
DOIs
Publication statusPublished - 2013

Cite this

Fu, Ying ; Mukhamedova, Nigora ; Ip, Sally Chi Ieng ; D'Souza, Wilissa Rose ; Henley, Katya J ; Ditommaso, Tia Marie ; Kesani, Rajitha ; Ditiatkovski, Michael ; Jones, Lynelle Karyn ; Lane, Rachael M ; Jennings, Garry L R ; Smyth, Ian Macleod ; Kile, Benjamin ; Sviridov, Dimitri. / ABCA12 regulates ABCA1-dependent cholesterol efflux from macrophages and the development of atherosclerosis. In: Cell Metabolism. 2013 ; Vol. 18, No. 2. pp. 225-238.
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title = "ABCA12 regulates ABCA1-dependent cholesterol efflux from macrophages and the development of atherosclerosis",
abstract = "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 Lxrbeta. Overexpression of Lxrbeta reversed the effects. Mechanistically, Abca12 deficiency did not affect expression of genes involved in cholesterol metabolism. Instead, a physical association between Abca1, Abca12, and Lxrbeta proteins was established. Abca12 deficiency enhanced interaction between Abca1 and Lxrbeta 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 LXRbeta-dependent posttranscriptional mechanism.",
author = "Ying Fu and Nigora Mukhamedova and Ip, {Sally Chi Ieng} and D'Souza, {Wilissa Rose} and Henley, {Katya J} and Ditommaso, {Tia Marie} and Rajitha Kesani and Michael Ditiatkovski and Jones, {Lynelle Karyn} and Lane, {Rachael M} and Jennings, {Garry L R} and Smyth, {Ian Macleod} and Benjamin Kile and Dimitri Sviridov",
year = "2013",
doi = "10.1016/j.cmet.2013.07.003",
language = "English",
volume = "18",
pages = "225--238",
journal = "Cell Metabolism",
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}

Fu, Y, Mukhamedova, N, Ip, SCI, D'Souza, WR, Henley, KJ, Ditommaso, TM, Kesani, R, Ditiatkovski, M, Jones, LK, Lane, RM, Jennings, GLR, Smyth, IM, Kile, B & Sviridov, D 2013, 'ABCA12 regulates ABCA1-dependent cholesterol efflux from macrophages and the development of atherosclerosis' Cell Metabolism, vol. 18, no. 2, pp. 225-238. https://doi.org/10.1016/j.cmet.2013.07.003

ABCA12 regulates ABCA1-dependent cholesterol efflux from macrophages and the development of atherosclerosis. / Fu, Ying; Mukhamedova, Nigora; Ip, Sally Chi Ieng; D'Souza, Wilissa Rose; Henley, Katya J; Ditommaso, Tia Marie; Kesani, Rajitha; Ditiatkovski, Michael; Jones, Lynelle Karyn; Lane, Rachael M; Jennings, Garry L R; Smyth, Ian Macleod; Kile, Benjamin; Sviridov, Dimitri.

In: Cell Metabolism, Vol. 18, No. 2, 2013, p. 225-238.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - ABCA12 regulates ABCA1-dependent cholesterol efflux from macrophages and the development of atherosclerosis

AU - Fu, Ying

AU - Mukhamedova, Nigora

AU - Ip, Sally Chi Ieng

AU - D'Souza, Wilissa Rose

AU - Henley, Katya J

AU - Ditommaso, Tia Marie

AU - Kesani, Rajitha

AU - Ditiatkovski, Michael

AU - Jones, Lynelle Karyn

AU - Lane, Rachael M

AU - Jennings, Garry L R

AU - Smyth, Ian Macleod

AU - Kile, Benjamin

AU - Sviridov, Dimitri

PY - 2013

Y1 - 2013

N2 - 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 Lxrbeta. Overexpression of Lxrbeta reversed the effects. Mechanistically, Abca12 deficiency did not affect expression of genes involved in cholesterol metabolism. Instead, a physical association between Abca1, Abca12, and Lxrbeta proteins was established. Abca12 deficiency enhanced interaction between Abca1 and Lxrbeta 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 LXRbeta-dependent posttranscriptional mechanism.

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

UR - http://www.ncbi.nlm.nih.gov/pubmed/23931754

U2 - 10.1016/j.cmet.2013.07.003

DO - 10.1016/j.cmet.2013.07.003

M3 - Article

VL - 18

SP - 225

EP - 238

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

IS - 2

ER -