A Novel Function of Apolipoprotein E: Upregulation of ATP-Binding Cassette Transporter A1 Expression

Yanfeng Zhao,Xinping Chen,Hong Yang,Zhongmao Guo,Lichun Zhou,Emmanuel U Okoro,Vladimir N Uversky

doi:10.1371/journal.pone.0021453

Yanfeng Zhao, Xinping Chen + Show 5 more

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https://doi.org/10.1371/journal.pone.0021453

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Journal: PloS one	Publication Date: Jul 11, 2011
Citations: 55	License type: CC BY 4.0

Affiliation: Wuhan University, Meharry Medical College

Abstract

Despite the well known importance of apolipoprotein (Apo) E in cholesterol efflux, the effect of ApoE on the expression of ATP-binding cassette transporter A1 (ABCA1) has never been investigated. The objective of this study was to determine the effect of ApoE on ApoB-carrying lipoprotein-induced expression of ABCA1, a protein that mediates cholesterol efflux. Our data demonstrate that ApoB-carrying lipoproteins obtained from both wild-type and ApoE knockout mice induced ApoAI-mediated cholesterol efflux in mouse macrophages, which was associated with an enhanced ABCA1 promoter activity, and an increased ABCA1 mRNA and protein expression. In addition, these lipoproteins increased the level of phosphorylated specificity protein 1 (Sp1) and the amount of Sp1 bound to the ABCA1 promoter. However, all these inductions were significantly diminished in cells treated with ApoE-free lipoproteins, when compared to those treated with wild-type lipoproteins. Enrichment with human ApoE3 reversed the reduced inducibility of ApoE-free lipoproteins. Moreover, we observed that inhibition of Sp1 DNA-binding by mithramycin A diminished ABCA1 expression and ApoAI-mediated cholesterol efflux induced by ApoB-carrying lipoproteins, and that mutation of the Sp1-binding motif in the ABCA1 promoter region diminished ApoB-carrying lipoprotein-induced ABCA1 promoter activity. Collectively, these data suggest that ApoE associated with ApoB-carrying lipoproteins has an upregulatory role on ABCA1 expression, and that induction of Sp1 phosphorylation is a mechanism by which ApoE upregulates ABCA1 expression.

Highlights

Apolipoprotein (Apo) E is a major component of ApoB-carrying lipoproteins chylomicron remnants and very-low density lipoprotein (VLDL)
The level of ATP-binding cassette transporter A1 (ABCA1) mRNA and protein induced by E3/B lipoproteins was comparable to that induced by E+/B lipoproteins (Fig. 1A–1C)
These observations suggest that ApoE is indispensible for a full induction of ABCA1 expression by ApoB-carrying lipoproteins, i.e., ApoE has an upregulatory role in ApoB-carrying lipoprotein-induced ABCA1 expression

Summary

Introduction

Apolipoprotein (Apo) E is a major component of ApoB-carrying lipoproteins chylomicron remnants and very-low density lipoprotein (VLDL). It was initially recognized for its receptor binding function. Impaired ApoE recycling has been shown to result in intracellular cholesterol accumulation [3] Another mechanism for ApoEmediated cholesterol efflux involves lipid-poor ApoE [5,6]. Increasing evidence indicates that many extrahepatic cells, including macrophages, secret ApoE, which promotes macrophage cholesterol efflux by autocrine or paracrine In this process, lipid-poor ApoE accepts cholesterol released from macrophages [5,6], resulting in assembly of nascent high-density lipoproteins (HDL) [7,8]

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