Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Republic of Korea.
Free Radic Biol Med. 2019 Jun;137:143-157. doi: 10.1016/j.freeradbiomed.2019.04.030. Epub 2019 Apr 26.
Nonalcoholic steatohepatitis (NASH) is a common liver disease associated with metabolic disorders, including obesity and type 2 diabetes (T2D). Despite its worldwide prevalence, there are no effective drugs for the treatment of NASH. The progression of NASH is mainly accelerated by reactive oxygen species (ROS)-induced lipotoxicity. The transcription factor known as nuclear factor erythroid 2-related factor 2 (Nrf2) is pivotal for the elimination of ROS. Accordingly, activators of Nrf2 have been implicated as promising therapeutic targets for the treatment of NASH. Niclosamide (ethanolamine salt; NEN), a drug approved by the US Food and Drug Administration (USFDA), is currently used as an anthelmintic drug for the treatment of parasitic infections. Recently, NEN was shown to improve hepatic steatosis in high-fat diet (HFD)-fed mice. However, the underlying mechanism of its antioxidant function in NASH remains unknown. Here, we demonstrate that NEN induces AMPK-mediated phosphorylation of p62 at S351 that can lead to noncanonical Nrf2 activation. We also demonstrate that NEN protects cells and mouse liver from acute lipotoxic stress through activating p62-dependent Keap1-Nrf2 pathway. Taken together, NEN can be used for clinical applications and has the potential to provide a new therapeutic option for NASH.
非酒精性脂肪性肝炎（NASH）是一种与代谢紊乱相关的常见肝脏疾病，包括肥胖症和 2 型糖尿病（T2D）。尽管它在全球范围内普遍存在，但目前尚无治疗 NASH 的有效药物。NASH 的进展主要是由活性氧（ROS）诱导的脂毒性加速的。已知转录因子核因子红细胞 2 相关因子 2（Nrf2）对于消除 ROS 至关重要。因此，Nrf2 的激活剂被认为是治疗 NASH 的有前途的治疗靶点。尼氯硝唑（乙醇胺盐；NEN）是一种经美国食品和药物管理局（USFDA）批准的药物，目前用作治疗寄生虫感染的驱虫药。最近，NEN 被证明可以改善高脂肪饮食（HFD）喂养的小鼠的肝脂肪变性。然而，其在 NASH 中的抗氧化功能的潜在机制尚不清楚。在这里，我们证明 NEN 诱导 AMPK 介导的 p62 在 S351 处的磷酸化，这可能导致非典型 Nrf2 激活。我们还证明，NEN 通过激活 p62 依赖性 Keap1-Nrf2 途径来保护细胞和小鼠肝脏免受急性脂毒性应激。总之，NEN 可用于临床应用，并有可能为 NASH 提供新的治疗选择。
