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The Journal of Lipid Research, Vol. 40, 486-494, March 1999
Copyright © 1999 by Lipid Research, Inc.

Original Article

Multiple dysfunctions of two apolipoprotein A-I variants, apoA-I(R160L)_Oslo and apoA-I(P165R), that are associated with hypoalphalipoproteinemia in heterozygous carriers

Correspondence to: Arnold von Eckardstein

ApoA-I(R160L)_Oslo and apoA-I(P165R) are naturally occurring apolipoprotein (apo) A-I variants that are associated with low HDL-cholesterol in heterozygous carriers. We characterized the capacity of these variants to bind lipid, to activate lecithin:cholesterol acyltransferase (LCAT), and to promote efflux of biosynthetic cholesterol from porcine aortic smooth muscle cells (SMCs) or exogenous cholesterol from lipid-loaded mouse peritoneal macrophages. During cholate dialysis, normal apoA-I and both variants associated completely with dipalmitoylphosphatidylcholine (DPPC) and formed rLpA-I of identical size. However, both apoA-I(P165R) and apoA-I(R160L)_Oslo showed a reduced capacity to clear a turbid emulsion of dimyristoylphosphatidylcholine (DMPC). Compared to normal apoA-I, the LCAT-cofactor activity of apoA-I(P165R) and apoA-I(R160L)_Oslo as defined by the ratio of V_max to appK_m was reduced significantly by 62% and 29%, respectively (here and throughout the text, the apparent K_m is given as Michaelis-Menten kinetics do not take particle binding into account and therefore would result in errors with an interfacial enzyme such as LCAT; V_max estimates are not affected by this error). ApoA-I/DPPC complexes induced biphasic cholesterol efflux from SMCs with a fast and a slow efflux component. Compared to rLpA-I reconstituted with wild type apoA-I, rLpA-I with apoA-I(P165R) or apoA-I(R160L)_Oslo were significantly less effective in promoting cholesterol efflux from SMCs in incubations of 10 min duration but equally effective in incubations of 6 h duration. Lipid-free apoA-I did not induce efflux of biosynthetic cholesterol from SMCs but induced hydrolysis of cholesteryl esters and cholesterol efflux from acetyl-LDL-loaded mouse peritoneal macrophages. In the lipid-free form, both apoA-I variants promoted normal cholesterol efflux from murine peritoneal macrophages.

We conclude that amino acid residues arginine 160 and proline 165 of apoA-I contribute to the formation of a domain that is very important for initial lipid binding and contributes to LCAT-activation and promotion of initial cholesterol efflux but not to the stabilization of preformed rLpA-I.—Daum, U., T. P. Leren, C. Langer, A. Chirazi, P. Cullen, P. H. Pritchard, G. Assmann, and A. von Eckardstein. Multiple dysfunctions of two apolipoprotein A-I variants, apoA-I(R160L)_Oslo and apoA-I(P165R), that are associated with hypoalphalipoproteinemia in heterozygous carriers. J. Lipid Res. 1999. 40: 486–494.

Supplementary key words: familial hypoalphalipoproteinemia, apoA-I variants, cholesterol efflux, LCAT, reverse cholesterol transport

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