title: Apolipoprotein E4 is deficient in inducing macrophage ABCA1 expression and stimulating the Sp1 signaling pathway.
abstract: ATP binding cassette A1 (ABCA1) is a membrane protein that promotes cellular cholesterol efflux. Using RAW 264.7 macrophages, we studied the relative effects of apolipoprotein (apo) E3 and apoE4 on ABCA1 and on the signaling pathway that regulates its expression. Both lipid-associated and lipid-free apoE4 forms induced ~30% lower levels of ABCA1 protein and mRNA than apoE3 forms. Phosphorylated levels of phosphoinositol 3-kinase (PI3K), protein kinase Cζ (PKCζ) and specificity protein 1 (Sp1) were also lower when treated with apoE4 compared to apoE3. The reduced ability of apoE4 to induce ABCA1 expression, PKCζ and Sp1 phosphorylation were confirmed in human THP-1 monocytes/macrophages. Sequential phosphorylation of PI3K, PKCζ and Sp1 has been suggested as a mechanism for upregulation of ABCA1 expression. Both apoE3 and apoE4 reduced total cholesterol and cholesterol esters in lipid-laden RAW 264.7 cells, and induced apoAI-mediated cholesterol efflux. However, the cholesterol esters and cholesterol efflux in apoE4-treated cells were ~50% and ~24% lower, respectively, compared to apoE3-treated cells. Accumulation of cholesterol esters in macrophages is a mechanism for foam cell formation. Thus the reduced ability of apoE4 to activate the PI3K-PKCζ-Sp1 signaling pathway and induce ABCA1 expression likely impairs cholesterol ester removal, and increases foam cell formation.
authors.affiliation: Department of Physiology, Meharry Medical College, Nashville, Tennessee, United States of America.
authors.forename: Emmanuel Ugochukwu
authors.initials: EU
authors.lastname: Okoro
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Zhao
authors.forename: ZhongMao
authors.initials: Z
authors.lastname: Guo
authors.forename: Lichun
authors.initials: L
authors.lastname: Zhou
authors.forename: Xinghua
authors.initials: X
authors.lastname: Lin
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D053318:Apolipoprotein E3 / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000235:genetics*; D002784:Cholesterol / Q000378:metabolism; D005487:Foam Cells; D005786:Gene Expression Regulation; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism*
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D016329:Sp1 Transcription Factor; D002784:Cholesterol; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C