Discovery of a natural small-molecule AMP-activated kinase activator that alleviates nonalcoholic steatohepatitis
Jin Chen, Xu Li, Xue-Qing Zhang, Xue Liu, Zixuan Zhang, Qiumei Zhu, Jianyu Liu, Muhammad Omer Iqbal, Ning Ding, Chang‐Lun Shao, Mei‐Yan Wei, Yuchao Gu
Abstract
Abstract Non-alcoholic steatohepatitis (NASH) is a primary cause of cirrhosis and hepatocellular carcinoma. Unfortunately, there is no approved drug treatment for NASH. AMP-activated kinase (AMPK) is an important metabolic sensor and whole-body regulator. It has been proposed that AMPK activators could be used for treating metabolic diseases such as obesity, type 2 diabetes and NASH. In this study, we screened a marine natural compound library by monitoring AMPK activity and found a potent AMPK activator, candidusin A ( CHNQD-0803 ). Further studies showed that CHNQD-0803 directly binds recombinant AMPK with a K D value of 4.728 × 10 –8 M and activates AMPK at both molecular and intracellular levels. We then investigated the roles and mechanisms of CHNQD-0803 in PA-induced fat deposition, LPS-stimulated inflammation, TGF-β-induced fibrosis cell models and the MCD-induced mouse model of NASH. The results showed that CHNQD-0803 inhibited the expression of adipogenesis genes and reduced fat deposition, negatively regulated the NF-κB-TNFα inflammatory axis to suppress inflammation, and ameliorated liver injury and fibrosis. These data indicate that CHNQD-0803 as an AMPK activator is a novel potential therapeutic candidate for NASH treatment.