| Autor: |
Panagiotis Fotakis, Ioanna Tiniakou, Andreas K. Kateifides, Christina Gkolfinopoulou, Angeliki Chroni, Efstratios Stratikos, Vassilis I. Zannis, Dimitris Kardassis |
| Jazyk: |
angličtina |
| Rok vydání: |
2013 |
| Předmět: |
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| Zdroj: |
Journal of Lipid Research, Vol 54, Iss 12, Pp 3293-3302 (2013) |
| Druh dokumentu: |
article |
| ISSN: |
0022-2275 |
| DOI: |
10.1194/jlr.M043489 |
| Popis: |
We studied the significance of four hydrophobic residues within the 225–230 region of apoA-I on its structure and functions and their contribution to the biogenesis of HDL. Adenovirus-mediated gene transfer of an apoA-I[F225A/V227A/F229A/L230A] mutant in apoA-I−/− mice decreased plasma cholesterol, HDL cholesterol, and apoA-I levels. When expressed in apoA-I−/− × apoE−/− mice, approximately 40% of the mutant apoA-I as well as mouse apoA-IV and apoB-48 appeared in the VLDL/IDL/LDL. In both mouse models, the apoA-I mutant generated small spherical particles of pre-β- and α4-HDL mobility. Coexpression of the apoA-I mutant and LCAT increased and shifted the-HDL cholesterol peak toward lower densities, created normal αHDL subpopulations, and generated spherical-HDL particles. Biophysical analyses suggested that the apoA-I[225–230] mutations led to a more compact folding that may limit the conformational flexibility of the protein. The mutations also reduced the ability of apoA-I to promote ABCA1-mediated cholesterol efflux and to activate LCAT to 31% and 66%, respectively, of the WT control. Overall, the apoA-I[225–230] mutations inhibited the biogenesis of-HDL and led to the accumulation of immature pre-β- and α4-HDL particles, a phenotype that could be corrected by administration of LCAT. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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