Estradiol binding prevents ApoB-100 misfolding in electronegative LDL(-)

Roberto Brunelli, Gabor Balogh, Graziella Costa, Marco De Spirito, Giulia Greco, Giampiero Mei, Eleonora Nicolai, Laszlo Vigh, Fulvio Ursini, Tiziana Parasassi

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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. 17α-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.

Original languageEnglish
Pages (from-to)7297-7302
Number of pages6
Issue number34
Publication statusPublished - Aug 31 2010

ASJC Scopus subject areas

  • Biochemistry

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    Brunelli, R., Balogh, G., Costa, G., De Spirito, M., Greco, G., Mei, G., Nicolai, E., Vigh, L., Ursini, F., & Parasassi, T. (2010). Estradiol binding prevents ApoB-100 misfolding in electronegative LDL(-). Biochemistry, 49(34), 7297-7302.