Part of the HDL can be considered dysfunctional, and this malfunction makes it not really behave as antiatherogenic. Know you a relatively simple method that allows us to measure their functionality
Hello,
At the present time the question is difficult answer. There are either different cell-based assays availble allowing to measure some of the CV-relevant HDL functions, such as cholesterol efflux, oxidative stress or inflammatory response, or mass psectrometry-based approches allowing the identification of certain post translationnal modifications (PTM) associatied with HDL dysfunction mostly induced by MPO, such as apoA1 chorination, oxidation, nitrosylation or glycation. Given the clicnial failure of CETP inhibitors despite a great effect in cholesterol efflux models, I personnaly believe that cholesterol efflux models may well not be relevant to human physiopahtology. We do currently work on inflammatory cell-based model where we test the ability of HDL to promote cytokine release from human macrophages trying to relate this with specfic MS signatures on apoA-1, but we haven't reached any firm conclusion yet. I guess that in the future, the identification by MS of specific apoA-1 PTM has a good chance to compete out the cell-based assays, but there is currently no definite gold standard nor simple methods for HDL function assessment.
S. Hazen has really pionneered this field with several major publications which could be of interest to you in case you haven't been through already.
Kind regards,
Nicolas
Thank you Ali,
The presentation from Rader is very interesting and recommended, but I'd like some other methodology to differentiate the antiatherogenic HDL from dysfunctional HDL (prooxidant and proatherogenic), and if possible quantify dysfunctional HDL.
I agree with Nicolas Vuilleumier that we are just starting to understand the role of HDL in health and disease. In addition to the proteomic composition of HDL, the phospholipid content of HDL seems to be of particular importance because it is most strongly linked to cholesterol efflux capability of mature HDL. Post translational modifications of HDL like carbamylation and oxidation are important in the inflamed vessel wall, but affect only a minor fraction of circulating HDL. Currently assessing cholesterol efflux property of HDL is thought to be a key metric of HDL functionality, (i) since removing cholesterol (and oxidized cholesterol) from lipid rafts and cell membranes is thought to interfere with TLR4 signalling, thereby dampening the inflammatory response. Moreover, removing oxysterols from endothelial cells activates eNOS and seems inhibit the expression of adhesion molecules in endothelial cells.
We made a symple test with diclorofluorestein, but previously separate the differents lipoproteins by FPLC. If you are interestedsend me a e mail.
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