title: Estradiol binding prevents ApoB-100 misfolding in electronegative LDL(-).
abstract: Seeking for a modified lipoprotein present in plasma that could account for the atherogenic effect of high cholesterol, several years ago electronegative LDL(-) was identified. The peculiar feature of LDL(-) is an apoprotein misfolding that triggers the formation of aggregates, perfectly fitting in size the subendothelial droplets observed in early phases of atherogenesis. Apoprotein misfolding was therefore proposed as a possible atherogenic modification. LDL(-) can be spontaneously produced in vitro by plasma incubation through phospholipid hydrolysis catalyzed by the activity of endogenous phospholipases. As a consequence, apoprotein is misfolded. 17beta-Estradiol (E2), a specific ligand to apoB-100, was used to unravel the relationship between negative charge of the lipoprotein and apoprotein structural/conformational shift. Although E2 addition to plasma does not prevent LDL(-) generation nor phospholipase activity, it deeply stabilizes apoB-100 structure, thus preventing its structural and conformational shift. Apoprotein stabilization extends to lipids. Indeed, while a loosening of lipid packing is observed together with apoprotein misfolding, conversely, when E2 stabilizes apoprotein, lipid structure is preserved. Finally, even in the presence of LDL(-), the E2-stabilized LDL is resistant to aggregation, unambiguously demonstrating that misfolding, but not negative charge, primes aggregation. In conclusion, electronegative charge and misfolding are independent and distinct features of LDL(-), and apoprotein misfolding rather than the increase in the negative charge emerges both as a valid biomarker and as an appealing pharmacological and nutritional target.
authors.affiliation: Dipartimento di Ostetricia e Ginecologia, Università di Roma Sapienza, Roma, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Brunelli
authors.forename: Gabor
authors.initials: G
authors.lastname: Balogh
authors.forename: Graziella
authors.initials: G
authors.lastname: Costa
authors.forename: Marco
authors.initials: M
authors.lastname: De Spirito
authors.forename: Giulia
authors.initials: G
authors.lastname: Greco
authors.forename: Giampiero
authors.initials: G
authors.lastname: Mei
authors.forename: Eleonora
authors.initials: E
authors.lastname: Nicolai
authors.forename: Laszlo
authors.initials: L
authors.lastname: Vigh
authors.forename: Fulvio
authors.initials: F
authors.lastname: Ursini
authors.forename: Tiziana
authors.initials: T
authors.lastname: Parasassi
mesh_terms: D053299:Apolipoprotein B-100 / Q000378:metabolism*; D001059:Apoproteins / Q000378:metabolism; D050197:Atherosclerosis; D008078:Cholesterol, LDL / Q000378:metabolism*; D004958:Estradiol / Q000378:metabolism*; D006868:Hydrolysis; D008074:Lipoproteins / Q000378:metabolism; D010740:Phospholipases / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism
chemical_list: D053299:Apolipoprotein B-100; D001059:Apoproteins; D008078:Cholesterol, LDL; D008074:Lipoproteins; D010743:Phospholipids; D004958:Estradiol; D010740:Phospholipases