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Originally published In Press as doi:10.1194/jlr.M700158-JLR200 on August 10, 2007

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Journal of Lipid Research, Vol. 48, 2385-2395, November 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

ApoA-I cleaved by transthyretin has reduced ability to promote cholesterol efflux and increased amyloidogenicity

Márcia Almeida Liz*,{dagger}, Cláudio M. Gomes§, Maria João Saraiva*,{dagger} and Mónica Mendes Sousa1,*

* Molecular Neurobiology Group, Instituto de Biologia Molecular e Celular (IBMC), Porto, Portugal
{dagger} Instituto de Ciências Biomedicas Abel Salazar (ICBAS), University of Porto, Porto, Portugal
§ Instituto Tecnologia Química e Biológica, Universidade Nova de Lisboa, Oeiras, Portugal

Published, JLR Papers in Press, August 10, 2007.

1 To whom correspondence should be addressed. e-mail: msousa{at}ibmc.up.pt

A fraction of plasma transthyretin (TTR) circulates in HDL through binding to apolipoprotein A-I (apoA-I). Moreover, TTR is able to cleave the C terminus of lipid-free apoA-I. In this study, we addressed the relevance of apoA-I cleavage by TTR in lipoprotein metabolism and in the formation of apoA-I amyloid fibrils. We determined that TTR may also cleave lipidated apoA-I, with cleavage being more effective in the lipid-poor preß-HDL subpopulation. Upon TTR cleavage, discoidal HDL particles displayed a reduced capacity to promote cholesterol efflux from cholesterol-loaded THP-1 macrophages. In similar assays, TTR-containing HDL from mice expressing human TTR in a TTR knockout background had a decreased ability to perform reverse cholesterol transport compared with similar particles from TTR knockout mice, reinforcing the notion that cleavage by TTR reduces the ability of apoA-I to promote cholesterol efflux. As amyloid deposits composed of N-terminal apoA-I fragments are common in the atherosclerotic intima, we assessed the impact of TTR cleavage on apoA-I aggregation and fibrillar growth. We determined that TTR-cleaved apoA-I has a high propensity to form aggregated particles and that it formed fibrils faster than full-length apoA-I, as assessed by electron microscopy. Our results show that apoA-I cleavage by TTR may affect HDL biology and the development of atherosclerosis by reducing cholesterol efflux and increasing the apoA-I amyloidogenic potential.

Supplementary key words high density lipoprotein • reverse cholesterol transport • apolipoprotein A-I • apolipoprotein A-I amyloidosis • atherosclerosis


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