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Free Radic Biol Med. 2019 Jun;137:143-157. doi: 10.1016/j.freeradbiomed.2019.04.030. Epub 2019 Apr 26.

Repositioning of niclosamide ethanolamine (NEN), an anthelmintic drug, for the treatment of lipotoxicity.

Author information

1
Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
2
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.
3
Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. Electronic address: soohanbae@yuhs.ac.

Abstract

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.

KEYWORDS:

Lipotoxicity; NASH; NEN; Nrf2; p62

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