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.