CDB25:0003138 APOE — ABCA1
Experimentally validated in Human, Mixed species; Orthology-inferred in Human, Mouse, Rat, Frog, Zebrafish, Macaque, Pig, Dog, Cow, Chimp, Horse, Marmoset, Sheep
Title
Journal:; Year Published:
Abstract
Molecular interactions between apoE and ABCA1: impact on apoE lipidation.
Journal of lipid research, 2004; PubMed, Homo sapiens APOE — Homo sapiens ABCA1
ABSTRACT: Apolipoprotein E (apoE)/ABCA1 interactions were investigated in human intact fibroblasts induced with 22(R)-hydroxycholesterol and 9-cis-retinoic acid (stimulated cells). Here, we show that purified human plasma apoE3 forms a complex with ABCA1 in normal fibroblasts. Lipid-free apoE3 inhibited the binding of (125)I-apoA-I to ABCA1 more efficiently than reconstituted HDL particles (IC(50) = 2.5 +/- 0.4 microg/ml vs. 12.3 +/- 1.3 microg/ml). ApoE isoforms showed similar binding for ABCA1 and exhibited identical kinetics in their abilities to induce ABCA1-dependent cholesterol efflux. Mutation of ABCA1 associated with Tangier disease (C1477R) abolished both apoE3 binding and apoE3-mediated cholesterol efflux. Analysis of apoE3-containing particles generated during the incubation of lipid-free apoE3 with stimulated normal cells showed nascent apoE3/cholesterol/phospholipid complexes that exhibited prebeta-electrophoretic mobility with a particle size ranging from 9 to 15 nm, whereas lipid-free apoE3 incubated with ABCA1 mutant (C1477R) cells was unable to form such particles. These results demonstrate that 1). apoE association with lipids reduced its ability to interact with ABCA1; 2). apoE isoforms did not affect apoE binding to ABCA1; 3). apoE-mediated ABCA1-dependent cholesterol efflux was not affected by apoE isoforms in fibroblasts; and 4). the lipid translocase activity of ABCA1 generates apoE-containing high density-sized lipoprotein particles. Thus, ABCA1 is essential for the biogenesis of high density-sized lipoprotein containing only apoE particles in vivo.
Astrocyte׳s endogenous apoE generates HDL-like lipoproteins using previously synthesized cholesterol through interaction with ABCA1.
Brain research, 2014; PubMed, Homo sapiens APOE — Rattus norvegicus Abca1
ABSTRACT: Apolipoprotein E (apoE) in the brain is predominantly synthesized in and secreted from astrocytes to generate apoE-containing high-density lipoprotein-like particles (apoE/HDL). However, the mechanism underlying generation of apoE/HDL has not been completely understood. The newly synthesized cholesterol, which is synthesized in rat astrocytes within 24 h using [(3)H]-acetate as a cholesterol precursor, was assembled as lipoproteins with densities of 1.12-1.17 g/mL (higher density HDL), although apoE was secreted as lipoproteins with lower densities of 1.08-1.12 g/mL from the cells. This finding suggests that the newly synthesized cholesterol is released without the association with apoE, which is like that from apoE-deficient mouse (apoE-KO) astrocytes. The cholesterol released from rat astrocytes at 3 days after the onset of its synthesis (previously synthesized cholesterol) was assembled as apoE/HDL with the densities of 1.08-1.12 g/mL (lower density HDL). These findings indicate that the endogenous apoE participates in the release of previously synthesized cholesterol but not newly synthesized one. Whereas, exogenously added human apoE induced release of both newly synthesized and previously synthesized cholesterols to generate apoE/HDL with lower density, suggesting that the cellular pool of cholesterol released by endogenous and exogenous apoE is different. The endogenous apoE was distributed in the caveolin-1-rich domain along with ATP-binding cassette transporter A1 (ABCA1) in the membrane fraction and immuno-precipitated using an anti-ABCA1 antibody. However, this is not the case for ABCA1-KO astrocytes. These findings suggest that endogenous apoE generates lower density HDL to produce more lipidated HDL using previously synthesized cholesterol through the interaction with ABCA1 in caveolin-1-rich domain of astrocytes.