Journal of Lipid Research, Vol 38, 2314-2321, Copyright © 1997 by Lipid Research, Inc.

ARTICLES

High density lipoprotein particle size restriction in apolipoprotein A- I(Milano) transgenic mice

JK Bielicki, TM Forte, MR McCall, LJ Stoltzfus, G Chiesa, CR Sirtori, G Franceschini and EM Rubin
Ernest Orlando Lawrence Berkeley National Laboratory, Life Sciences Division, University of California, Berkeley 94720, USA.

Human carriers of apolipoprotein A-I(Milano) (Arg173 --> Cys substitution in apolipoprotein A-I) are characterized by an HDL deficiency in which small, dense HDL accumulate in plasma. Because affected individuals are heterozygous for this mutation, the full impact of apolipoprotein A-I(Milano) (apoA-I(Milano)) on HDL- cholesterol metabolism is unknown. In this study, apoA-I(Milano) transgenic mice were used to evaluate the extent of apoA-I(Milano) dimerization and HDL particle size restriction in the absence of wild- type apoA-I. Murine apoA-I knockout mice were utilized to express apoA- I(Milano) and human apoA-II in the presence of wild-type, human apoA-I (apoA-IMilano/A-Iwt/A-II) and in its absence (apoA-IMilano/A-II). Plasma HDL-cholesterol concentrations were similar (30 mg/dl) in both lines of apoA-I(Milano) transgenic mice. In the apoA-IMilano/A-Iwt/A-II phenotype, 14% of the apoA-I(Milano) formed homodimers and 33% formed heterodimers with apoA-II. ApoA-I(Milano) homodimers increased by 71% in the apoA-IMilano/A-II transgenics and was associated with an abundance of small, 7.6-nm HDL3-sized particles compared to the 9.5, 8.3, and 7.6-nm-sized particles in apoA-IMilano/A-Iwt/A-II mice. The unesterified cholesterol/cholesteryl ester mole ratio of HDL was elevated by 45% in apoA-IMilano/A-Iwt/A-II mice and by 90% in apoA- IMilano/A-II transgenics compared to wild-type (human apoA-I/A-II). Both apoA-I(Milano) transgenics possessed normal levels of plasma LCAT activity, but endogenous cholesterol esterification rates were reduced by 50% compared to controls. Thus, HDL particle size restriction was not the result of impaired LCAT activation; rather, dimerization of apoA-I(Milano) limited the esterification of cholesterol on endogenous HDL. In the absence of wild-type apoA-I, the more extensive dimerization of apoA-I(Milano) severely limited cholesteryl ester accumulation on plasma HDL accounting for the abundance of small, 7.6- nm HDL3 particles in apoA-IMilano/A-II mice.
CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				G. L. Hortin, N. Seam, and G. T. Hoehn Bound Homocysteine, Cysteine, and Cysteinylglycine Distribution between Albumin and Globulins Clin. Chem., December 1, 2006; 52(12): 2258 - 2264. [Abstract] [Full Text] [PDF]

				D. D. O. Martin, M. S. Budamagunta, R. O. Ryan, J. C. Voss, and M. N. Oda Apolipoprotein A-I Assumes a "Looped Belt" Conformation on Reconstituted High Density Lipoprotein J. Biol. Chem., July 21, 2006; 281(29): 20418 - 20426. [Abstract] [Full Text] [PDF]

				B. Olchawa, B. A. Kingwell, A. Hoang, L. Schneider, O. Miyazaki, P. Nestel, and D. Sviridov Physical Fitness and Reverse Cholesterol Transport Arterioscler. Thromb. Vasc. Biol., June 1, 2004; 24(6): 1087 - 1091. [Abstract] [Full Text] [PDF]

				C. Parolini, G. Chiesa, Y. Zhu, T. Forte, S. Caligari, E. Gianazza, M. G. Sacco, C. R. Sirtori, and E. M. Rubin Targeted Replacement of Mouse Apolipoprotein A-I with Human ApoA-I or the Mutant ApoA-IMilano. EVIDENCE OF APOA-IM IMPAIRED HEPATIC SECRETION J. Biol. Chem., February 7, 2003; 278(7): 4740 - 4746. [Abstract] [Full Text] [PDF]

				P. G. Frank and Y. L. Marcel Apolipoprotein A-I: structure;-function relationships J. Lipid Res., June 1, 2000; 41(6): 853 - 872. [Abstract] [Full Text]

				G. Franceschini, L. Calabresi, G. Chiesa, C. Parolini, C. R. Sirtori, M. Canavesi, and F. Bernini Increased Cholesterol Efflux Potential of Sera From ApoA-IMilano Carriers and Transgenic Mice Arterioscler. Thromb. Vasc. Biol., May 1, 1999; 19(5): 1257 - 1262. [Abstract] [Full Text] [PDF]