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J. Biol. Chem., Vol. 280, Issue 27, 25383-25387, July 8, 2005

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Apolipoprotein A-V-heparin Interactions

IMPLICATIONS FOR PLASMA LIPOPROTEIN METABOLISM^*

Aivar Lookene, Jennifer A. Beckstead¶, Solveig Nilsson, Gunilla Olivecrona, and Robert O. Ryan¶||

From the Department of Medical Biosciences/Physiological Chemistry, Umeå University, SE-901 87 Umeå, Sweden, the Department of Gene Technology, Tallinn Technical University, Tallinn 12618, Estonia, and the^¶ Lipid Biology in Health and Disease Research Group, Children's Hospital Oakland Research Institute, Oakland, California 94609

Transgenic and gene disruption experiments in mice have revealed that apolipoprotein (apo) A-V is a potent regulator of plasma triglyceride (TG) levels. To investigate the molecular basis of apoA-V function, the ability of isolated recombinant apoA-V to modulate lipoprotein lipase (LPL) activity was examined in vitro. With three distinct lipid substrate particles, including very low-density lipoprotein (VLDL), a TG/phospholipid emulsion, or dimyristoylphosphatidylcholine liposomes, apoA-V had little effect on LPL activity. In the absence or presence apolipoprotein C-II, apoA-V marginally inhibited LPL activity. On the other hand, apoA-V-dimyristoylphosphatidylcholine disc particles bound to heparin-Sepharose and were specifically eluted upon application of a linear gradient of NaCl. The interaction of apoA-V with sulfated glycosaminoglycans was further studied by surface plasmon resonance spectroscopy. ApoA-V showed strong binding to heparin-coated chips, and binding was competed by free heparin. ApoA-V enrichment enhanced binding of apoC-II-deficient chylomicrons and VLDL to heparin-coated chips. When LPL was first bound to the heparin-coated chip, apoA-V-enriched chylomicrons showed binding. Finally, human pre- and post-heparin plasma samples were subjected to immunoblot analysis with anti-apoA-V IgG. No differences in the amount of apoA-V present were detected. Taken together, the results show that apoA-V lipid complexes bind heparin and, when present on TG-rich lipoprotein particles, may promote their association with cell surface heparan sulfate proteoglycans. Through such interactions, apoA-V may indirectly affect LPL activity, possibly explaining its inverse correlation with plasma TG levels.

Received for publication, February 10, 2005 , and in revised form, May 6, 2005.

^* This work was supported by grants from the Swedish Medical Science Council (number 12203), the King Gustaf V Research foundation, and Grant HL 073061 from the National Institutes of Health.

^|| To whom correspondence should be addressed. Tel./Fax: 510-450-7645; E-mail: rryan{at}chori.org.

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