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Autophagy. 2018;14(1):120-133. doi: 10.1080/15548627.2017.1327942. Epub 2017 Nov 25.

Prdx1 (peroxiredoxin 1) deficiency reduces cholesterol efflux via impaired macrophage lipophagic flux.

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a Immune and Vascular Cell Network Research Center, National Creative Initiatives , Department of Life Sciences , Ewha Womans University , Seoul , Korea.
b Cardiovascular Division , Department of Medicine , Washington University School of Medicine , St. Louis , MO , USA.
c Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience & Biotechnology , Daejeon , Korea.
d Korea Aging Research Center, Korea Research Institute of Bioscience and Biotechnology , Daejeon , Korea.
e Division of Cardiology , Department of Internal Medicine , Yonsei University College of Medicine , Seoul , Korea.
f Department of Life Science and Research Center for Cell Homeostasis , Ewha Womans University , Seoul , Korea ; Global Top5 Research program, Ewha Womans University , Seoul , Korea.
g Department of Anatomy , School of Medicine, Ewha Womans University , Seoul , Korea.
h Department of Medicine , University of California, San Diego , San Diego , CA , USA.
i Department of Molecular Medicine , Ewha Womans University School of Medicine , Seoul , Korea.
j Department of Microbiology and Immunology , McGill Faculty of Medicine , Montréal , Canada.
k Department of Life Science , College of Natural Sciences and Research Institute for Natural Sciences, Hanyang University , Seoul , Korea.


Oxidative stress activates macroautophagy/autophagy and contributes to atherogenesis via lipophagic flux, a form of lipid removal by autophagy. However, it is not known exactly how endogenous antioxidant enzymes are involved in lipophagic flux. Here, we demonstrate that the antioxidant PRDX1 (peroxiredoxin 1) has a crucial role in the maintenance of lipophagic flux in macrophages. PRDX1 is more highly expressed than other antioxidant enzymes in monocytes and macrophages. We determined that Prdx1 deficiency induced excessive oxidative stress and impaired maintenance of autophagic flux in macrophages. Prdx1-deficient macrophages had higher intracellular cholesterol mass and lower cholesterol efflux compared with wild type. This perturbation in cholesterol homeostasis was due to impaired lipophagic cholesterol hydrolysis caused by excessive oxidative stress, resulting in the inhibition of free cholesterol formation and the reduction of NR1H3 (nuclear receptor subfamily 1, group H, member 3) activity. Notably, impairment of both lipophagic flux and cholesterol efflux was restored by the 2-Cys PRDX-mimics ebselen and gliotoxin. Consistent with this observation, apoe -/- mice transplanted with bone marrow from prdx1-/-apoe-/- mice had increased plaque formation compared with apoe-/- BM-transplanted recipients. This study reveals that PRDX1 is crucial to regulating lipophagic flux and maintaining macrophage cholesterol homeostasis against oxidative stress. We suggest that PRDX1-dependent control of oxidative stress may provide a strategy for treating atherosclerosis and autophagy-related human diseases.


atherosclerosis; lipophagy; macrophage; oxidative stress; peroxiredoxin 1

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