Dataset Information

ATP-binding cassette A1 and cholesterol transfer protein Aster-A promote an asymmetric cholesterol distribution in the plasma membrane.

ABSTRACT: Cholesterol is a major and essential component of the mammalian cell plasma membrane (PM), and the loss of cholesterol homeostasis leads to various pathologies. Cellular cholesterol uptake and synthesis are regulated by a cholesterol sensor in the endoplasmic reticulum (ER). However, it remains unclear how changes in the cholesterol level of the PM are recognized. Here we show that the sensing of cholesterol in the PM depends on ATP-binding cassette A1 (ABCA1) and the cholesterol transfer protein Aster-A, which cooperatively maintain the asymmetric transbilayer cholesterol distribution in the PM. We demonstrate that ABCA1 translocates (flops) cholesterol from the inner leaflet of the PM to the outer leaflet to maintain a low inner leaflet cholesterol level. We also found when inner cholesterol levels were increased, Aster-A was recruited to the PM-ER contact site to transfer cholesterol to the ER. These results suggest that ABCA1 could promote an asymmetric cholesterol distribution to suppress Aster-A recruitment to the PM-ER contact site to maintain intracellular cholesterol homeostasis.

SUBMITTER: Ogasawara F

PROVIDER: S-EPMC9747601 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

ABCA1 and cholesterol transfer protein Aster-A promote an asymmetric cholesterol distribution in the plasma membrane.

Ogasawara Fumihiko F Ueda Kazumitsu K

The Journal of biological chemistry 20221114 12

Cholesterol is a major and essential component of the mammalian cell plasma membrane (PM), and the loss of cholesterol homeostasis leads to various pathologies. Cellular cholesterol uptake and synthesis are regulated by a cholesterol sensor in the endoplasmic reticulum (ER). However, it remains unclear how changes in the cholesterol level of the PM are recognized. Here, we show that the sensing of cholesterol in the PM depends on ABCA1 and the cholesterol transfer protein Aster-A, which cooperat ...[more]

PMID: 36395885

Similar Datasets

Project description:ObjectivesCholesterol efflux capacity (CEC) is the main antiatherogenic function of high-density lipoprotein (HDL). ATP-binding-cassette A1 (ABCA1) membrane transporter initiates cholesterol export from arterial macrophages to pre-β HDL particles fostering their maturation; in turn, those accept cholesterol through ABCG1-mediated export. Impaired pre-β HDL maturation may disrupt the collaborative function of the two transporters and adversely affect atherosclerosis. Statins exert atheroprotective functions systemically and locally on plaque. We here evaluated associations between ABCA1-CEC, coronary atherosclerosis and cardiovascular risk and the influence of statins on those relationships in rheumatoid arthritis (RA).MethodsEvaluation with computed tomography angiography was undertaken in 140 patients and repeated in 99 after 6.9 ± 0.3 years. Events comprising cardiovascular death, acute coronary syndromes, stroke, claudication, revascularization and heart failure were recorded. ABCA1-CEC and ABCG1-CEC were evaluated in J774A.1 macrophages and Chinese hamster ovary (CHO) cells respectively and expressed as percentage of effluxed over total intracellular cholesterol. Covariates in all cardiovascular event risk and plaque outcome models included atherosclerotic cardiovascular disease (ASCVD) risk score and high-density lipoprotein cholesterol.ResultsABCA1-CEC negatively correlated with ABCG1-CEC (r = -0.167, p = 0.049). ABCA1-CEC associated with cardiovascular risk (adjusted hazard ratio 2.05 [95%CI 1.20-3.48] per standard deviation [SD] increment). There was an interaction of ABCA1-CEC with time-varying statin use (p = 0.038) such that current statin use inversely associated with risk only in patients with ABCA1-CEC below the upper tertile. ABCA1-CEC had no main effect on plaque or plaque progression; instead, ABCA1-CEC (per SD) associated with fewer baseline total plaques (adjusted rate ratio [aRR] 0.81, [95%CI 0.65-1.00]), noncalcified plaques (aRR 0.78 [95%CI 0.61-0.98]), and vulnerable low-attenuation plaques (aRR 0.41 [95%CI 0.23-0.74]) in statin users, and more low-attenuation plaques (aRR 1.91 [95%CI 1.18-3.08]) in nonusers (p-for-interaction = 0.018, 0.011, 0.025 and < 0.001 respectively). Moreover, ABCA1-CEC (per SD) associated with greater partially/fully-calcified plaque progression (adjusted odds ratio 3.07 [95%CI 1.20-7.86]) only in patients not exposed to statins during follow-up (p-for-interaction = 0.009).ConclusionIn patients with RA, higher ABCA1-CEC may reflect a proatherogenic state, associated with enhanced cardiovascular risk. Statin use may unmask the protective impact of ABCA1-mediated cholesterol efflux on plaque formation, progression and cardiovascular risk.

Dataset Information

ATP-binding cassette A1 and cholesterol transfer protein Aster-A promote an asymmetric cholesterol distribution in the plasma membrane.

Publications

ABCA1 and cholesterol transfer protein Aster-A promote an asymmetric cholesterol distribution in the plasma membrane.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets