Estradiol binding prevents ApoB-100 misfolding in electronegative LDL(-).
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.
Brunelli
Roberto
R
Dipartimento di Ostetricia e Ginecologia, Università di Roma Sapienza, Roma, Italy.
Balogh
Gabor
G
Costa
Graziella
G
De Spirito
Marco
M
Greco
Giulia
G
Mei
Giampiero
G
Nicolai
Eleonora
E
Vigh
Laszlo
L
Ursini
Fulvio
F
Parasassi
Tiziana
T
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
D053299:Apolipoprotein B-100; D001059:Apoproteins; D008078:Cholesterol, LDL; D008074:Lipoproteins; D010743:Phospholipids; D004958:Estradiol; D010740:Phospholipases