Submitted on March 30, 2007
Revised on July 25, 2007
Accepted on August 9, 2007
APOA-I cleaved by transthyretin has reduced ability to promote cholesterol efflux and increased amyloidogenicity
Márcia Almeida Liz, Cláudio M. Gomes, Maria João Saraiva, and Mónica Mendes Sousa
Molecular Neurobiology, Instituto de Biologia Molecular e Celular-IBMC, Porto, Porto 4150-180
Corresponding Author: msousa{at}ibmc.up.pt
A fraction of plasma transthyretin (TTR) circulates in high-density lipoproteins (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, being cleavage more effective in the lipid-poor pre-ß-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, when compared to similar particles from TTR knockout mice, reinforcing that cleavage by TTR reduces the ability of apoA-I to promote cholesterol efflux. As amyloid deposits composed by 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 impact on HDL biology and in the development of atherosclerosis, by reducing cholesterol efflux and increasing the apoA-I amyloidogenic potential.
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