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

Abstract

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 preb-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.-Liz, M. A., C. M. Gomes, M. J. Saraiva, and M. M. Sousa. ApoA-I cleaved by transthyretin has reduced ability to promote cholesterol efflux and increased amyloidogenicity. J. Lipid Res. 2007Res. . 48: 2385Res. -2395

Modified Apolipoprotein (apo) A-I by Artificial Sweetener Causes Severe Premature Cellular Senescence and Atherosclerosis with Impairment of Functional and Structural Properties of apoA-I in Lipid-Free and Lipid-Bound State

“…ApoA-I is well-known for its antioxidant ability in both lipid-free and lipid-bound states (Cho et al, 2006). Similarly, Liz et al (2007) reported that cleavage of apoA-I (26 kDa) by transthyretin is associated with loss of unique features of dysfunctional HDL and an increase in amyloidogenicity. They showed loss of C-terminal (226-243) in apoA-I is associated with a severe decrease in the alpha-helix and an increase in beta-strands and random coils in apoA-I.…”

Sampling the N-terminal proteome of human blood

“…Proteolytic products of certain intracellular events, including apoptotic and necrotic cell death (25), may also be released into the blood, where they may serve as useful markers of these processes. Proteolytic fragments of normal plasma proteins are also directly implicated in the pathogenesis of certain diseases, such as amyloidoses and atherosclerosis (26,27). Within our N-terminal peptide dataset, we find examples of all of these classes ( Table 1).…”

Aboard transthyretin: From transport to cleavage

“…ApoA-I was subsequently identified as the unique plasma TTR substrate (51). The relevance of apoA-I cleavage by TTR was analyzed and it was shown that it impacts on HDL biology and in the development of atherosclerosis by reducing the ability of apoA-I to promote cholesterol efflux and by increasing apoA-I amyloidogenicity (52). Nevertheless, the in vivo impact of TTR in atherosclerosis requires further investigation.…”