A small molecule targeting ALOX12-ACC1 ameliorates nonalcoholic steatohepatitis in mice and macaques.

Abstract

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.

• Authors: Xiao-Jing Zhang, Yan-Xiao Ji, Xu Cheng, Yanjie Cheng, Hailong Yang, Junyong Wang, Ling-Ping Zhao, Yong-Ping Huang, Dating Sun, Hui Xiang, Li-Jun Shen, Peng-Long Li, Jun-Peng Ma, Rui-Feng Tian, Juan Yang, Xinxin Yao, Haibo Xu, Rufang Liao, Li Xiao, Peng Zhang, Xin Zhang, Guang-Nian Zhao, Xi Wang, Man-Li Hu, Song Tian, Juan Wan, Jingjing Cai, Xinliang Ma, Qingbo Xu, Yibin Wang, Rhian M Touyz, Peter P Liu, Rohit Loomba, Zhi-Gang She, Hongliang Li
• Journal: Science translational medicine (Sci Transl Med) Vol. 13 Issue 624 Pg. eabg8116 (12 15 2021) ISSN: 1946-6242 [Electronic] United States
• PMID: 34910548 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ACC1 protein, mouse
• Acetyl-CoA Carboxylase

Topics

• Acetyl-CoA Carboxylase
• Animals
• Liver (metabolism)
• Macaca (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Non-alcoholic Fatty Liver Disease (drug therapy, metabolism)