Discovery of an insulin‐induced gene binding compound that ameliorates nonalcoholic steatohepatitis by inhibiting sterol regulatory element‐binding protein–mediated lipogenesis
Shi‐You Jiang, Xinglin Yang, Zimo Yang, Juewan Li, Meng‐Qiang Xu, Yu-Xiu Qu, Jingjie Tang, Yun‐Feng Li, Liguo Wang, Yi‐Wen Shao, Xin‐Yuan Meng, Huili Hu, Bao‐Liang Song, Yu Rao, Wei Qi
Abstract
Abstract Background and Aims NASH is associated with high levels of cholesterol and triglyceride (TG) in the liver; however, there is still no approved pharmacological therapy. Synthesis of cholesterol and TG is controlled by sterol regulatory element‐binding protein (SREBP), which is found to be abnormally activated in NASH patients. We aim to discover small molecules for treating NASH by inhibiting the SREBP pathway. Approach and Results Here, we identify a potent SREBP inhibitor, 25‐hydroxylanosterol (25‐HL). 25‐HL binds to insulin‐induced gene (INSIG) proteins, stimulates the interaction between INSIG and SCAP, and retains them in the endoplasmic reticulum, thereby suppressing SREBP activation and inhibiting lipogenesis. In NASH mouse models, 25‐HL lowers levels of cholesterol and TG in serum and the liver, enhances energy expenditure to prevent obesity, and improves insulin sensitivity. 25‐HL dramatically ameliorates hepatic steatosis, inflammation, ballooning, and fibrosis through down‐regulating the expression of lipogenic genes. Furthermore, 25‐HL exhibits both prophylactic and therapeutic efficacies of alleviating NASH and atherosclerosis in amylin liver NASH model diet‐treated Ldlr−/− mice, and reduces the formation of cholesterol crystals and associated crown‐like structures of Kupffer cells. Notably, 25‐HL lowers lipid contents in serum and the liver to a greater extent than lovastatin or obeticholic acid. 25‐HL shows a good safety and pharmacokinetics profile. Conclusions This study provides the proof of concept that inhibiting SREBP activation by targeting INSIG to lower lipids could be a promising strategy for treating NASH. It suggests the translational potential of 25‐HL in human NASH and demonstrates the critical role of SREBP‐controlled lipogenesis in the progression of NASH by pharmacological inhibition.