Structure and function of the apoA-IV T347S and Q360H common variants |
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Authors: | Monica Gomaraschi Silvia Pozzi Alberto Barbiroli Elda Favari Guido Franceschini Laura Calabresi |
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Institution: | a Center E. Grossi Paoletti, Department of Pharmacological Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy b Centre for Cardiovascular Genetics, Department of Medicine, University College London, 5 University St., London WC1E 6JF, UK c Department of Molecular and Agroalimentary Sciences, Universitá degli Studi di Milano, Via Celoria 2, 20133 Milano, Italy d Department of Pharmacological and Biological Sciences, and Applied Chemistries, University of Parma, Viale G.P. Usberti, 27/A, 43100 Parma, Italy |
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Abstract: | Human apolipoprotein A-IV (apoA-IV) is involved in chylomicron assembly and secretion, and in reverse cholesterol transport. Several apoA-IV isoforms exist, the most common in Caucasian populations being apoA-IV-1a (T347S) and apoA-IV-2 (Q360H). The objective of the present study was to investigate the impact of these common aminoacid substitutions on the ability of apoA-IV to bind lipids, to promote cell cholesterol efflux via ABCA1, and to maintain endothelial homeostasis. Recombinant forms of wild-type apoA-IV, apoA-IV Q360H, and apoA-IV T347S were produced in Escherichia coli. ApoA-IV Q360H and apoA-IV T347S showed a slightly higher α-helical content compared to wild-type apoA-IV, and associated with phospholipids faster than wild-type apoA-IV. The capacity to promote ABCA1-mediated cholesterol efflux was significantly greater for the apoA-IV T347S than the other apoA-IV isoforms. No differences were observed in the ability of apoA-IV isoforms to inhibit the production of VCAM-1 and IL-6 in TNFα-stimulated endothelial cells. In conclusion, the apoA-IV T347S common variant has increased lipid binding properties and cholesterol efflux capacity, while the apoA-IV Q360H variant has only slightly increased lipid binding properties. The two common aminoacid substitutions have no effect on the ability of apoA-IV to maintain endothelial homeostasis. |
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Keywords: | Apolipoprotein A-IV High density lipoproteins Cellular cholesterol efflux Vascular endothelium |
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