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- Title
A small molecule targeting ALOX12-ACC1 ameliorates nonalcoholic steatohepatitis in mice and macaques.
- Authors
Zhang, Xiao-Jing; Ji, Yan-Xiao; Cheng, Xu; Cheng, Yanjie; Yang, Hailong; Wang, Junyong; Zhao, Ling-Ping; Huang, Yong-Ping; Sun, Dating; Xiang, Hui; Shen, Li-Jun; Li, Peng-Long; Ma, Jun-Peng; Tian, Rui-Feng; Yang, Juan; Yao, Xinxin; Xu, Haibo; Liao, Rufang; Xiao, Li; Zhang, Peng
- Abstract
Halting a driver of hepatocyte lipotoxicity: Despite its prevalence and seriousness, nonalcoholic steatohepatitis (NASH) still lacks a treatment. Zhang et al. show that the lipoxygenase ALOX12 increased NASH severity in mice, pigs, and macaques independent of its enzymatic function by stabilizing ACC1, altering lysosomal degradation, increasing hepatocyte inflammation, and impeding ketogenesis. In a separate manuscript, Zhang et al. demonstrate that a small molecule effectively disrupted the ALOX12-ACC1 interaction in vivo, halting the development of liver steatosis, inflammation, and fibrosis in mice and macaque models of NASH without eliciting the hyperlipidemia that typically results from inhibiting the more canonical enzymatic function of ACC1. Nonalcoholic steatohepatitis (NASH) is a progressive liver disease and has become a leading indication for liver transplantation in the United States. The development of effective therapies for NASH is a major unmet need. Here, we identified a small molecule, IMA-1, that can treat NASH by interrupting the arachidonate 12-lipoxygenase (ALOX12)–acetyl-CoA carboxylase 1 (ACC1) interaction. IMA-1 markedly blocked diet-induced NASH progression in both male mice and Cynomolgus macaque therapeutic models. The anti-NASH efficacy of IMA-1 was comparable to ACC inhibitor in both species. Protein docking simulations and following functional experiments suggested that the anti-NASH effects of IMA-1 were largely dependent on its direct binding to a pocket in ALOX12 proximal to its ACC1-interacting surface instead of inhibiting ALOX12 lipoxygenase activity. IMA-1 treatment did not elicit hyperlipidemia, a known side effect of direct inhibition of ACC enzymatic activity, in both mice and macaques. These findings provide proof of concept across multiple species for the use of small molecule–based therapies for NASH.
- Subjects
UNITED States; NON-alcoholic fatty liver disease; SMALL molecules; DISEASE progression; MACAQUES; MOLECULAR docking; SIGNAL recognition particle receptor
- Publication
Science Translational Medicine, 2021, Vol 13, Issue 624, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abg8116