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Cholesterol Hydroperoxide Generation, Translocation, and Reductive Turnover in Biological Systems

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Abstract

Cholesterol is like other unsaturated lipids in being susceptible to peroxidative degradation upon exposure to strong oxidants like hydroxyl radical or peroxynitrite generated under conditions of oxidative stress. In the eukaryotic cell plasma membrane, where most of the cellular cholesterol resides, peroxidation leads to membrane structural and functional damage from which pathological states may arise. In low density lipoprotein, cholesterol and phospholipid peroxidation have long been associated with atherogenesis. Among the many intermediates/products of cholesterol oxidation, hydroperoxide species (ChOOHs) have a number of different fates and deserve special attention. These fates include (a) damage-enhancement via iron-catalyzed one-electron reduction, (b) damage containment via two-electron reduction, and (c) inter-membrane, inter-lipoprotein, and membrane-lipoprotein translocation, which allows dissemination of one-electron damage or off-site suppression thereof depending on antioxidant location and capacity. In addition, ChOOHs can serve as reliable and conveniently detected mechanistic reporters of free radical-mediated reactions vs. non-radical (e.g., singlet oxygen)-mediated reactions. Iron-stimulated peroxidation of cholesterol and other lipids underlies a newly discovered form of regulated cell death called ferroptosis. These and other deleterious consequences of radical-mediated lipid peroxidation will be discussed in this review.

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Abbreviations

Ch:

cholesterol

ChOOH:

cholesterol hydroperoxide

ChOH:

cholesterol hydroxide

ChOX:

oxidized cholesterol species

cAMP:

cyclic-AMP

LOOH:

lipid hydroperoxide

PLOOH:

phospholipid hydroperoxide

GPx4:

glutathione peroxidase type-4

GSH:

reduced glutathione

LDL:

low density lipoprotein

oxLDL:

oxidatively modified LDL

RBC:

red blood cell

SePx:

selenoperoxidase

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Acknowledgements

Studies in the authors’ laboratories were supported by USPHS Grants CA72630, TW001386, and CA70823 (to A.W.G.) and Polish National Center for Science Grant NCN-2014/13/B/NZ3/00833 (to W.K.). We thank Peter Geiger, Andrew Vila, Tamas Kriska, Vlad Levchenko, Jared Schmitt, Magda Niziolek, Kasia Wawak, and Anna Pilat for their many valuable contributions to the research supported by these grants.

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Authors and Affiliations

  1. Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Albert W. Girotti & Witold Korytowski

  2. Department of Biophysics, Jagiellonian University, Krakow, Poland

    Witold Korytowski

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  1. Albert W. Girotti
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Correspondence to Albert W. Girotti.

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Girotti, A.W., Korytowski, W. Cholesterol Hydroperoxide Generation, Translocation, and Reductive Turnover in Biological Systems. Cell Biochem Biophys 75, 413–419 (2017). https://doi.org/10.1007/s12013-017-0799-0

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  • DOI: https://doi.org/10.1007/s12013-017-0799-0

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