A novel truncated form of apolipoprotein A-I transported by dense LDL is increased in diabetic patients

Judit Cubedo, Teresa Padró, Maisa García-Arguinzonis, Gemma Vilahur, Inka Miñambres, Jose María Pou, Juan Ybarra, Lina Badimon

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    11 Citations (Scopus)

    Abstract

    Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc. Diabetic (DM) patients have exacerbated atherosclerosis and high CVD burden. Changes in lipid metabolism, lipoprotein structure, and dysfunctional HDL are characteristics of diabetes. Our aim was to investigate whether serum ApoA-I, the main protein in HDL, was biochemically modified in DM patients. By using proteomic technologies, we have identified a 26 kDa ApoA-I form in serum. MS analysis revealed this 26 kDa form as a novel truncated variant lacking amino acids 1-38, ApoA-IΔ(1-38). DM patients show a 2-fold increase in ApoA-IΔ(1-38) over nondiabetic individuals. ApoA-IΔ(1-38) is found in LDL, but not in VLDL or HDL, with an increase in LDL3 and LDL4 subfractions. To identify candidate mechanisms of ApoA-I truncation, we investigated potentially involved enzymes by in silico data mining, and tested the most probable molecule in an established animal model of diabetes. We have found increased hepatic cathepsin D activity as one of the potential proteases involved in ApoA-I truncation. Cathepsin D-cleaved ApoA-I exhibited increased LDL binding affinity and decreased antioxidant activity against LDL oxidation. In conclusion, we show for the first time: a) presence of a novel truncated ApoA-I form, ApoA-IΔ(1-38), in human serum; b) ApoA-IΔ(1-38) is transported by LDL; c) ApoA-IΔ(1-38) is increased in dense LDL fractions of DM patients; and d) cathepsin D-ApoA-I truncation may lead to ApoA-IΔ(1-38) binding to LDLs, increasing their susceptibility to oxidation and contributing to the high cardiovascular risk of DM patients.
    Original languageEnglish
    Pages (from-to)1762-1773
    JournalJournal of Lipid Research
    Volume56
    Issue number9
    DOIs
    Publication statusPublished - 1 Sep 2015

    Keywords

    • Hyperglycemia
    • Low density lipoprotein
    • Proteomics
    • Supplementary diabetes

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  • Cite this

    Cubedo, J., Padró, T., García-Arguinzonis, M., Vilahur, G., Miñambres, I., Pou, J. M., Ybarra, J., & Badimon, L. (2015). A novel truncated form of apolipoprotein A-I transported by dense LDL is increased in diabetic patients. Journal of Lipid Research, 56(9), 1762-1773. https://doi.org/10.1194/jlr.P057513