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: Roberto Brunelli, Gabor Balogh, Graziella Costa, Marco De Spirito, Giulia Greco, Giampiero Mei, Eleonora Nicolai, Laszlo Vigh, Fulvio Ursini, Tiziana Parasassi
• Journal: Biochemistry (Biochemistry) Vol. 49 Issue 34 Pg. 7297-302 (Aug 31 2010) ISSN: 1520-4995 [Electronic] United States
• PMID: 20669963 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoprotein B-100
• Apoproteins
• Cholesterol, LDL
• Lipoproteins
• Phospholipids
• Estradiol
• Phospholipases

Topics

• Apolipoprotein B-100 (metabolism)
• Apoproteins (metabolism)
• Atherosclerosis
• Cholesterol, LDL (metabolism)
• Estradiol (metabolism)
• Hydrolysis
• Lipoproteins (metabolism)
• Phospholipases (metabolism)
• Phospholipids (metabolism)