Atherosclerosis 184 (2006) 1–7 Review Structural modifications of HDL and functional consequences Gianna Ferretti a,∗ , Tiziana Bacchetti a , Anne N` egre-Salvayre b , Robert Salvayre b , Nicole Dousset c , Giovanna Curatola a a Institute of Biochemistry, Faculty of Medicine, University of Ancona, via Ranieri 1-60131, Italy b Inserm UMR-466 and Biochemistry Department, IFR-31, CHU Rangueil, Toulouse, France c FR 1744, University Paul Sabatier, Toulouse, France Received 21 April 2005; received in revised form 18 July 2005; accepted 1 August 2005 Available online 12 September 2005 Abstract High density lipoproteins (HDL) are susceptible to structural modifications mediated by various mechanisms including oxidation, glycation, homocysteinylation or enzymatic degradation. Structural alterations of HDL may affect their functional and atheroprotective properties. Oxidants, such as hypochlorous acid, peroxyl radicals, metal ions, peroxynitrite, lipoxygenases and smoke extracts, can alter both surface and core components of HDL. The formation of lipid peroxidation derivatives, such as thiobarbituric acid reactive substances, conjugated dienes, lipid hydroperoxides and aldehydes, is associated with changes of physical properties (fluidity, molecular order) and of apoprotein conformation. Non-enzymatic glycation, generally associated with lipoxidation, leads to form irreversible complexes called advanced glycation end products. These HDL modifications are accompanied with altered biological activities of HDL and associated enzymes, including paraoxonase, CETP and LCAT. Homocysteine-induced modification of HDL is mediated by homocysteine-thiolactone, and can be prevented by a calcium-dependent thiolactonase/paraoxonase. Tyrosylation of HDL induces the formation of dimers and trimers of apo AI, and alters cholesterol efflux. Phospholipases and proteolytic enzymes can also modify HDL lipid and apoprotein structure. HDL modification induces generally the loss of their anti-inflammatory and cytoprotective properties. This could play a role in the pathogenesis of atherosclerosis and neurodegenerative diseases such as Alzheimer’s disease. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Atherosclerosis; High density lipoprotein; Oxidation; Modification; Glycation Contents 1. Introduction .......................................................................................................... 1 2. Oxidation ............................................................................................................ 2 3. Non-enzymatic glycation .............................................................................................. 3 4. Homocysteinylation ................................................................................................... 4 5. Tyrosylation .......................................................................................................... 5 6. HDL modification induced by enzymes ................................................................................. 5 7. Conclusion ........................................................................................................... 5 References ........................................................................................................... 5 ∗ Corresponding author. Tel.: +39 071 220 4968; fax: +39 071 220 4398. E-mail address: g.ferretti@univpm.it (G. Ferretti). 1. Introduction Epidemiological and clinical studies of human diseases strongly suggest structure–function relationship for HDL. In 0021-9150/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2005.08.008