Significance of the hydrophobic residues 225-230 of apoA-I for the biogenesis of HDL.
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.
['Fotakis|Panagiotis|P|', 'Tiniakou|Ioanna|I|', 'Kateifides|Andreas K|AK|', 'Gkolfinopoulou|Christina|C|', 'Chroni|Angeliki|A|', 'Stratikos|Efstratios|E|', 'Zannis|Vassilis I|VI|', 'Kardassis|Dimitris|D|']
D000256:Adenoviridae D000818:Animals D016632:Apolipoprotein A-I D055598:Chemical Phenomena D057809:HEK293 Cells D006801:Humans D057927:Hydrophobic and Hydrophilic Interactions D008075:Lipoproteins, HDL D051379:Mice D009154:Mutation
apolipoprotein A-I mutations dyslipidemia high density lipoprotein biogenesis pre-β- and α-HDL particles