Original Article

Association of apolipoprotein E with ₂-macroglobulin in human plasma

Correspondence to: Jeffrey S. Cohn.

Apolipoprotein (apo) E plays a central role in the transport of lipids among different organs and cell types, whereas ₂-macroglobulin (₂M) is responsible for the binding and inactivation of plasma proteases, as well as the transport of various cytokines, growth factors, and hormones. In the present study, evidence is presented for direct binding of apoE with ₂M in human plasma, based on the observation that two-dimensional non-denaturing gradient gel electrophoretic separation of plasma resulted in co-migration of apoE with ₂M in a complex intermediate in size (18.5 nm in diameter) between low (LDL) and high density lipoproteins (HDL). ApoE associated with ₂M could be immunoprecipitated from plasma with anti-human ₂M antiserum. Purified apoE, labeled with ¹²⁵I, bound to native and methylamine-activated ₂M (₂M-MA) in vitro in a time- and concentration-dependent manner. ApoE bound to ₂M-MA with greater affinity than ₂M. The binding of apoE to both ₂M and ₂M-MA did not depend on the presence of lipid. Ingestion of an oral fat load resulted in a reduction in the amount of apoE associated with ₂M. Sphingomyelin vesicles and very low density lipoproteins (VLDL), but not phosphatidylcholine vesicles or HDL₃, inhibited the in vitro binding of ¹²⁵I-labeled apoE3 to ₂M and ₂M-MA. Binding of ¹²⁵I-labeled apoE3 was also partially inhibited by an excess of platelet-derived growth factor and ß-amyloid protein, but not interferon-. Subjects with an apoE 4/4 phenotype had less apoE associated with ₂M in plasma than subjects with an apoE 3/3 or 2/2 phenotype, corresponding to reduced in vitro binding of apoE4 with ₂M or ₂M-MA.

Although the functional significance of apoE binding to ₂M remains to be determined, the present results demonstrate that: 1) apoE is non-covalently bound to ₂M in human plasma, 2) ₂M-MA has a greater capacity to bind apoE than ₂M, 3) various proteins or lipoproteins known to bind apoE or ₂M can potentially affect the interaction of apoE with ₂M, and 4) association of apoE with ₂M or ₂M-MA is dependent on apoE phenotype.—Krimbou, L., M. Tremblay, J. Davignon, and J. S. Cohn. Association of apolipoprotein E with ₂-macroglobulin in human plasma. J. Lipid Res. 1998. 39: 2373–2386.

Supplementary key words: atherosclerosis, Alzheimer's disease, high density lipoprotein, LRP

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