Peroxiredoxin 6 Confers Protection Against Nonalcoholic Fatty Liver Disease Through Maintaining Mitochondrial Function

• Published in: Antioxidants & redox signaling Vol. 31; no. 5; p. 387
• Main Authors: Lee, Dong Hun, Jung, Yu Yeon, Park, Mi Hee, Jo, Mi Ran, Han, Sang Bae, Yoon, Do Young, Roh, Yoon Seok, Hong, Jin Tae
• Format: Journal Article
• Language: English
• Published: United States 10.08.2019
• Subjects: NAFLD; PRDX6; oxidative stress; Notch; mitochondrial integrity
• ISSN: 1557-7716
• DOI: 10.1089/ars.2018.7544

Nonalcoholic fatty liver disease (NAFLD) is accompanied by excessive reactive oxygen species (ROS) production, which has been suggested in several studies to link with mitochondrial function. However, the mechanistic role of ROS-mediated regulation of mitochondrial function in NAFLD has not been elucidated. Since peroxiredoxin 6 (PRDX6) is the only member of the antioxidant PRDX family that translocates to damaged mitochondria, we investigated the PRDX6-mediated antisteatotic mechanism using genetically modified mice and cells. PRDX6 mice were more protective to lipid accumulation, liver injury, and insulin resistance after a high-fat diet. Mechanistically, PRDX6 is required for induction of mitochondrial antioxidant action and beta-oxidation through maintaining mitochondrial integrity and subsequently prevents ROS-induced lipogenesis. Interestingly, oxidative stress-induced Notch signaling was suppressed in PRDX6 mice compared with wild-type mice, and genetic and pharmacological inhibition of Notch signaling improved lipid accumulation. Finally, PRDX knockdown or Notch inhibition reduced induction of mitophagy. PRDX6 antagonizes positive feedback loop between lipid accumulation and ROS production through regulation of mitochondrial function. For the first time, we demonstrate that PRDX6 maintains mitochondria integrity under oxidative stress and protects against NAFLD progression by inhibition of Notch signaling. This study describes a novel molecular mechanism underlying the antisteatotic activity of PRDX6, which may be a new therapeutic strategy for the treatment of NAFLD.