作者
Xiaojing Zhang,Yan‐Xiao Ji,Xu Cheng,Yun Cheng,Hailong Yang,Junyong Wang,Lei Zhao,Yaji Huang,Dating Sun,Hui Xiang,Lijun Shen,Penglong Li,Junpeng Ma,Ruifeng Tian,Juan Yang,Yao Xiao,Haibo Xu,Rufang Liao,Li Xiao,Peng Zhang,Xin Zhang,Guang‐Nian Zhao,Xi Wang,Manli Hu,Tian Shen,Juan Wan,Jingjing Cai,Xin‐Liang Ma,Qingbo Xu,Yibin Wang,Rhian M. Touyz,Peter P. Liu,Rohit Loomba,Zhi‐Gang She,Hongliang Li
摘要
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.