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Sirtori is correct to point out that the arginine to cysteine substitution is localized at amino-acid position 173 of the apo-AI-Milano molecule and not at position 179 as stated in our review. Also, the author rightly mentions earlier studies from his laboratory indicating that the formation of apoA-I-Milano dimers is linked to the increased stability of small HDL3-particles in subjects carrying the mutation1. Although this is an important point to consider, the low overall concentration of plasma HDL in patients with apoA-I Milano could still be due to increased clearance of other HDL particles, such as the monomeric forms of the protein or other HDL subclasses.
The studies by Sirtori and co-workers also indicate decreased interconversion of HDL3 from apoA-I Milano carriers to other HDL subclasses. Considering that the larger HDL lipoproteins, such as HDL2, can act as very potent acceptors for cholesterol efflux that might be quantitatively more important in HDL generation than the lipid-poorer HDL3, it seems unlikely to us that a decreased catabolism of HDL3 is responsible for the possibly anti-atherogenic effects of apoA-I Milano.
References
Franceschini, G. et al. Apolipoprotein AIMilano. Disulfide-linked dimers increase high density lipoprotein stability and hinder particle interconversion in carrier plasma. J. Biol. Chem. 265, 12224–12231 (1990).
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Linsel-Nitschke, P., Tall, A. Properties of ApoA-I Milano. Nat Rev Drug Discov 4, 698 (2005). https://doi.org/10.1038/nrd1554-c2
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DOI: https://doi.org/10.1038/nrd1554-c2