Recent clinical trials reported that increasing high-density lipoprotein-cholesterol (HDL-C) levels does not improve cardiovascular outcomes. We hypothesize that HDL proteome dynamics determine HDL cardioprotective functions. In this study, we characterized proteome profiles in HDL subclasses and established their functional connection. Mouse plasma was fractionized by fast protein liquid chromatography, examined for protein, cholesterial, phospholipid and trigliceride content. Small, medium and large (S/M/L)-HDL subclasseses were collected for proteomic analysis by mass spectrometry. Fifty-one HDL proteins (39 in S-HDL, 27 in M-HDL and 29 in L-HDL) were identified and grouped into 4 functional categories (lipid metabolism, immune response, coagulation, and others). Eleven HDL common proteins were identified in all HDL subclasses. Sixteen, 3 and 7 proteins were found only in S-HDL, M-HDL and L-HDL, respectively. We established HDL protein dynamic distribution in S/M/L-HDL and developed a model of protein composition change during HDL maturation. We found that cholesterol efflux and immune response are essential functions for all HDL particles, and amino acid metabolism is a special function of S-HDL, whereas anti-coagulation is special for M-HDL. Pon1 is recruited into M/L-HDL to provide its antioxidative function. ApoE is incorporated into L-HDL to optimize its cholesterial clearance function. Next, we acquired HDL proteome data from Pubmed and identified 12 replicated proteins in human and mouse HDL particle. Finally, we extracted 3 shared top moleccular pathways (LXR/RXR, FXR/RXR and acute phase response) for all HDL particles and 5 top disease/bio-functions differentially related to S/M/L-HDL subclasses, and presented one top net works for each HDL subclass. We conclude that beside their essencial functions of cholesterol efflux and immune response, HDL aquired antioxidative and cholesterol clearance functions by recruiting Pon1 and ApoE during HDL maturation.

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Notes/Citation Information

Published in Redox Biology, v. 24, 101222, p. 1-13.

© 2019 The Authors. Published by Elsevier B.V.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).

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Funding Information

This work was supported in part by the National Institutes of Health grants HL67033, HL77288, HL82774, HL-110764, HL130233, HL131460, DK104114, DK113775 to HW and HL131460 to HW/EC/XFY. YLZ is supported by a fellowship from China Scholarship Council.

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Supplementary data to this article can be found online at https://doi.org/10.1016/j.redox.2019.101222.

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