Natural human apoA-I mutations L141RPisa and L159RFIN alter HDL structure and functionality and promote atherosclerosis development in mice. Issue 1 (November 2015)

• Record Type: Journal Article
• Authors: Tiniakou, Ioanna; Kanaki, Zoi; Georgopoulos, Spiros; Chroni, Angeliki; Van Eck, Miranda; Fotakis, Panagiotis; Zannis, Vassilis I.; Kardassis, Dimitris
• Is Part Of: Atherosclerosis. Volume 243:Issue 1(2015)
• Page Start: 77
• Page End: 85
• Publication Date: 2015-11
• Subjects: Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2015.08.028
• Languages: English
• ISSNs: 0021-9150

Abstract

<abstract xml:lang="en" abstract-type="author" id="abs0010"> <title id="sectitle0010">Abstract</title> <sec> <title id="sectitle0015">Objective</title> <p id="abspara0010">Mutations in human apolipoprotein A-I (apoA-I) are associated with low high-density lipoprotein (HDL) cholesterol levels and pathological conditions such as premature atherosclerosis and amyloidosis. In this study we functionally characterized two natural human apoA-I mutations, L141R<sub>Pisa</sub> and L159R<sub>FIN</sub>, <italic>in vivo</italic>.</p> </sec> <sec> <title id="sectitle0020">Methods</title> <p id="abspara0015">We generated transgenic mice expressing either wild-type (WT) or the two mutant forms of human apoA-I on a mouse apoA-I<sup>−/−</sup> background and analyzed for abnormalities in their lipid and lipoprotein profiles. HDL structure and functionality, as well as atherosclerosis development following a 14-week high-fat diet were assessed in these mice.</p> </sec> <sec> <title id="sectitle0025">Results</title> <p id="abspara0020">The expression of either apoA-I mutant was associated with markedly reduced serum apoA-I (<10% of WT apoA-I), total and HDL-cholesterol levels (∼20% and ∼7% of WT apoA-I, respectively) and the formation of few small size HDL particles with preβ2 and α3, α4 electrophoretic mobility. HDL particles containing either of the two apoA-I mutants exhibited attenuated anti-oxidative properties as indicated by their inability to prevent low-density lipoprotein oxidation, and by decreased activities of paraoxonase-1 and platelet-activating factor acetylhydrolase. However, the apoA-I(L141R)<sub>Pisa</sub> or apoA-I(L159R)<sub>FIN</sub>-containing HDL particles demonstrated increased capacity to promote ATP-Binding Cassette Transporter A1-mediated cholesterol efflux from macrophages. Expression of apoA-I(L141R)<sub>Pisa</sub> or apoA-I(L159R)<sub>FIN</sub> mutations in mice was associated with increased diet-induced atherosclerosis compared to either WT apoA-I transgenic or apoA-I<sup>−/−</sup> mice.</p> </sec> <sec> <title id="sectitle0030">Conclusions</title> <p id="abspara0025">These findings suggest that natural apoA-I mutations L141R<sub>Pisa</sub> and L159R<sub>FIN</sub> affect the biogenesis and the functionality of HDL <italic>in vivo</italic> and predispose to diet-induced atherosclerosis in the absence of any other genetic defect.</p> </sec> </abstract>