15-Lipoxygenase-mediated modification of high-density lipoproteins impairs SR-BI- and ABCA1-dependent cholesterol efflux from macrophages.
Elevated plasma levels of high-density lipoprotein cholesterol (HDL-C) are atheroprotective and HDL-dependent reverse cholesterol transport has been related to this effect. HDL particles may, however, undergo modifications that affect their biological activities. Lipoxygenases (LOs) belong to a family of lipid peroxidizing enzymes; among them, reticulocyte-type 15-lipoxygenase (15-LO-1) appears to play a pathophysiological role in atherosclerosis, as its expression is increased in atherosclerotic plaques and it has been shown to oxidize low-density lipoproteins to an atherogenic form. In this work we investigated the impact of in vitro 15-lipoxygenase-catalyzed modification of HDL3 on their ability to act as cholesterol acceptor and found that 15-LO-modified HDL3 were less effective in mediating cholesterol efflux from lipid-laden J774 cells. A reduced binding of 15-LO-modified HDL3 to scavenger receptor class B, type I (SR-BI), due to HDL apoproteins cross-linking, explained, at least in part, the observed reduction of cholesterol efflux. In addition, ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux was also reduced, as a consequence of pre-beta-particles loss after HDL3 modification. These results suggest that 15-lipoxygenase might induce structural alterations of HDL3 particles that impair their capability of triggering reverse cholesterol transport.
Pirillo
Angela
A
Department of Pharmacological Sciences, University of Milan, Milan, Italy. angela.pirillo@unimi.it
Uboldi
Patrizia
P
Kuhn
Hartmut
H
Catapano
Alberico L
AL
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D002460:Cell Line; D002784:Cholesterol / Q000031:analogs & derivatives / Q000378:metabolism*; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D011817:Rabbits; D051122:Scavenger Receptors, Class B / Q000378:metabolism*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008075:Lipoproteins, HDL; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D017392:Thiobarbituric Acid Reactive Substances; C023511:cholesteryl oleyl ether; D002784:Cholesterol; D001093:Arachidonate 15-Lipoxygenase