WZ66,a novel acetyl-CoA carboxylase inhibitor,alleviates nonalcoholic steatohepatitis(NASH)in mice  

作　　者：Ying-sheng Gao Min-yi Qian Qiang-qiang Wei Xu-bin Duan Shi-lei Wang Hai-yang Hu Jun Liu Chu-yue Pan Shuo-quan Zhang Lian-wen Qi Jin-pei Zhou Hui-bin Zhang Li-rui Wang 

机构地区：[1]School of Basic Medicine and Clinical Pharmacy,State Key Laboratory of Natural Medicines,China Pharmaceutical University,Nanjing 211198,China [2]College of pharmacy and chemistry,Dali University,Dali 671003,China [3]Center of Drug Discovery,State Key Laboratory of Natural Medicines,China Pharmaceutical University,Nanjing 210009,China [4]School of Traditional Chinese Pharmacy,State Key Laboratory of Natural Medicines,China Pharmaceutical University,Nanjing 211198,China [5]School of life Science and Technology,China Pharmaceutical University,Nanjing 211198,China [6]Clinical Metabolomics Center,China Pharmaceutical University,Nanjing 211198,China [7]Department of Medicinal Chemistry,China Pharmaceutical University,Nanjing 211198,China

出　　处：《Acta Pharmacologica Sinica》2020年第3期336-347,共12页中国药理学报（英文版）

基　　金：This study was supported by the National Natural Science Foundation of China(81700748 to LRW);by funding the“Double First-Class”University Project(CPU2018GF10 to LRW and CPU2018GY31 to LRW);“National Key R&D Program of China”(2018YFC1704900 and 2018YFC1704905 to LRW).

摘　　要：The global prevalence of nonalcoholic steatohepatitis(NASH)increases incredibly.NASH ends up to advanced liver disease,which is highly threatening to human health.Currently,treatment of NASH is very limited.Acetyl-CoA carboxylases(ACC1/ACC2)are proved as effective drug targets for NASH.We aimed to develop novel ACC inhibitors and evaluate their therapeutic value for NASH prevention.ACC inhibitors were obtained through structure-based drug design,synthesized,screened from ACC enzymatic measurement platform and elucidated in cell culture-based assays and animal models.The lipidome and microbiome analysis were integrated to assess the effects of WZ66 on lipids profiles in liver and plasma as well as gut microbiota in the intestine.WZ66 was identified as a novel ACC1/2 inhibitor.It entered systemic circulation rapidly and could accumulate in liver.WZ66 alleviated NASH-related liver features including steatosis,Kupffer cells and hepatic stellate cells activation in diet-induced obese mice.The triglycerides(TGs)and other lipids including diglycerides(DGs),phosphatidylcholine(PC)and sphingomyelin(SM)were decreased in WZ66-treated mice as evidenced by lipidome analysis in livers.The lipids profiles in plasma were also altered with WZ66 treatment.Plasma TG were moderately increased,while the activation of SREBP1c was not detected.WZ66 also downregulated the abundance of Allobaculum,Mucispirillum and Prevotella genera as well as Mucispirillum schaedleri species in gut microbiota.WZ66 is an ideal lead compound and a potential drug candidate deserving further investigation in the therapeutics of NASH.

关 键 词：non ALCOHOLIC STEATOHEPATITIS ACETYL-COA CARBOXYLASE WZ66 pharmacoki netics LIPIDOME gut MICROBIOME 

分 类 号：R575.5[医药卫生—消化系统]