1 College of Pharmacy and Medical Research Center, Department of Pharmacy Chungbuk National University, Cheongju, South Korea.
2 Department of Dental Hygiene, Gwangyang Health Sciences University, Gwangyang, South Korea.
Antioxid Redox Signal. 2019 Aug 10;31(5):387-402. doi: 10.1089/ars.2018.7544. Epub 2019 May 22.
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.
非酒精性脂肪性肝病（NAFLD）伴随着活性氧（ROS）的过度产生，这在几项研究中被认为与线粒体功能有关。然而，ROS 介导的线粒体功能调节在 NAFLD 中的机制作用尚未阐明。由于过氧化物还原酶 6（PRDX6）是抗氧化 PRDX 家族中唯一一种易位到受损线粒体的成员，因此我们使用基因修饰的小鼠和细胞研究了 PRDX6 介导的抗脂肪变性机制。PRDX6 小鼠在高脂肪饮食后对脂质积累、肝损伤和胰岛素抵抗更具保护作用。从机制上讲，PRDX6 通过维持线粒体完整性来诱导线粒体抗氧化作用和β-氧化，从而防止 ROS 诱导的脂肪生成。有趣的是，与野生型小鼠相比，PRDX6 小鼠中的氧化应激诱导的 Notch 信号受到抑制，而 Notch 信号的遗传和药理学抑制可改善脂质积累。最后，PRDX6 敲低或 Notch 抑制减少了线粒体自噬的诱导。PRDX6 通过调节线粒体功能拮抗脂质积累和 ROS 产生之间的正反馈循环。我们首次证明，PRDX6 在氧化应激下维持线粒体完整性，并通过抑制 Notch 信号来防止 NAFLD 进展。本研究描述了 PRDX6 抗脂肪变性活性的新分子机制，这可能是治疗 NAFLD 的一种新的治疗策略。
