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Originally published In Press as doi:10.1074/jbc.M100326200 on July 2, 2001

J. Biol. Chem., Vol. 276, Issue 35, 33241-33248, August 31, 2001
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Interaction of Lecithin:Cholesterol Acyltransferase (LCAT)·alpha 2-Macroglobulin Complex with Low Density Lipoprotein Receptor-related Protein (LRP)
EVIDENCE FOR AN alpha 2-MACROGLOBULIN/LRP RECEPTOR-MEDIATED SYSTEM PARTICIPATING IN LCAT CLEARANCE*

Larbi KrimbouDagger , Michel MarcilDagger , Jean Davignon§, and Jacques Genest Jr.Dagger

From the Dagger  Cardiovascular Genetics Laboratory, McGill University Health Center/Royal Victoria Hospital, Montréal, Québec H3A 1A1, Canada and the § Hyperlipidemia and Atherosclerosis Research Group, Clinical Research Institute of Montreal, Montréal, Québec H2W 1R7

The reaction of lecithin:cholesterol acyltransferase (LCAT) with high density lipoproteins (HDL) is of critical importance in reverse cholesterol transport, but the structural and functional pathways involved in the regulation of LCAT have not been established. We present evidence for the direct binding of LCAT to alpha 2-macroglobulin (alpha 2M) in human plasma to form a complex 18.5 nm in diameter. Forty percent of plasma LCAT-HDL was associated with alpha 2M; moreover, most of the LCAT in cerebrospinal fluid and in the medium of cultured human hepatoma cell line was associated with alpha 2M. Purified recombinant human LCAT (rLCAT) labeled with 125I bound to native and methylamine-activated alpha 2M (alpha 2M-MA) in vitro in a time- and concentration-dependent manner, and this binding did not depend on the presence of lipid. rLCAT bound to alpha 2M-MA with greater affinity than to alpha 2M. Furthermore, rLCAT did not activate alpha 2M as phosphatidylcholine-specific phospholipase C does. Reconstituted HDL particles (LpA-I) inhibited the binding of rLCAT to alpha 2M more efficiently than native HDL3 did. LCAT associated with alpha 2M was enzymatically inactive under both endogenous and exogenous assay conditions. Purified rLCAT alone did not bind to low density lipoprotein receptor-related protein (LRP) as lipoprotein lipase (LPL) does; however, when rLCAT was combined with alpha 2M-MA to form a complex, binding, internalization, and degradation of rLCAT took place in LRP-expressing cells (LRP +/+) but not in cells deficient in LRP (LRP -/-). It is concluded that the binding of LCAT to alpha 2M inhibits its enzymatic activity. Furthermore, the finding supports the possibility that the LRP receptor can act in vivo to mediate clearance of the LCAT-alpha 2M complex and may significantly influence the bioavailability of LCAT.

* This work was supported by a grant from Pfizer within the framework of university/industry (Canadian Institutes of Health research program DOP40845 and CIHR grant MOP15042) and by La Succession J. A. De Sèves.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: McGill University Health Center/Royal Victoria Hospital, Cardiology Division M4.76, 687 Pine Ave. West, Montréal, Québec, Canada H3A 1A1. Tel.: 514-842-1231 ext. 4642; Fax: 514-843-2843; E-mail: jacques.genest@muhc.mcgill.ca.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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