title: The binding activity of the macrophage lipoprotein(a)/apolipoprotein(a) receptor is induced by cholesterol via a post-translational mechanism and recognizes distinct kringle domains on apolipoprotein(a).
abstract: Elevated plasma levels of lipoprotein(a) (Lp(a)) can be a risk factor for atherosclerosis, and the interaction of Lp(a) with cholesterol-loaded macrophages (foam cells) in atheromata may be important in Lp(a)-induced atherogenesis. We have previously shown that when cultured macrophages are loaded with cholesterol, they acquire the ability to internalize and lysosomally degrade Lp(a) via interaction between a novel cell-surface receptor activity and the apolipoprotein(a) (apo(a)) moiety of Lp(a). Herein we explore the cell-surface binding of recombinant apo(a) (r-apo(a)) by foam cells. Whereas the induction of degradation of r-apo(a) by cholesterol loading of macrophages depended on new protein synthesis, the induction of binding of r-apo(a) did not. Furthermore, J774 macrophages bound r-apo(a) in a cholesterol-regulatable and specific manner but degraded r-apo(a) poorly. Thus, the binding and internalization/degradation functions of the receptor activity are distinct. To explore which domains on r-apo(a) interact with the foam cell receptor, we conducted a series of competitive and direct binding and degradation experiments using 12 r-apo(a) constructs that differed in their content of specific kringle subtypes. These data, as well as complementary data with anti-apo(a) monoclonal antibodies, indicated that the region centered around kringle type IV, subtypes 6-7 (KIV6-7) is important in receptor binding. Remarkably, a cholesterol-induced receptor activity with similar structural specificity was also found on Chinese hamster ovary cells. In conclusion, the foam cell Lp(a)/apo(a) receptor consists of a cholesterol-regulatable binding activity and a short-lived component necessary for internalization or lysosomal degradation; the binding activity interacts with a distinct region of apo(a) that is different from that involved in competition for plasminogen binding.
authors.affiliation: Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA. iat1@colmbia.edu
authors.forename: G A
authors.initials: GA
authors.lastname: Keesler
authors.forename: B R
authors.initials: BR
authors.lastname: Gabel
authors.forename: C M
authors.initials: CM
authors.lastname: Devlin
authors.forename: M L
authors.initials: ML
authors.lastname: Koschinsky
authors.forename: I
authors.initials: I
authors.lastname: Tabas
mesh_terms: D000818:Animals; D016466:CHO Cells; D002784:Cholesterol / Q000494:pharmacology*; D006224:Cricetinae; D006801:Humans; D007700:Kinetics; D018082:Kringles; D017270:Lipoprotein(a) / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D018110:Receptors, Lipoprotein / Q000378:metabolism*
chemical_list: D017270:Lipoprotein(a); D018110:Receptors, Lipoprotein; C098070:lipoprotein A receptor; D002784:Cholesterol