Discovery of an insulin‐induced gene binding compound that ameliorates nonalcoholic steatohepatitis by inhibiting sterol regulatory element‐binding protein–mediated lipogenesis

HepatologyEarly View ORIGINAL ARTICLE Discovery of an insulin-induced gene binding compound that ameliorates nonalcoholic steatohepatitis by inhibiting sterol regulatory element-binding protein–mediated lipogenesis Shi-You Jiang, Shi-You Jiang Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, China Gene Editing Center, School of Life Science and Technology, ShanghaiTech University, Shanghai, ChinaSearch for more papers by this authorXinglin Yang, Xinglin Yang MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, ChinaSearch for more papers by this authorZimo Yang, Zimo Yang MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, ChinaSearch for more papers by this authorJue-Wan Li, Jue-Wan Li Gene Editing Center, School of Life Science and Technology, ShanghaiTech University, Shanghai, ChinaSearch for more papers by this authorMeng-Qiang Xu, Meng-Qiang Xu Gene Editing Center, School of Life Science and Technology, ShanghaiTech University, Shanghai, ChinaSearch for more papers by this authorYu-Xiu Qu, Yu-Xiu Qu Gene Editing Center, School of Life Science and Technology, ShanghaiTech University, Shanghai, ChinaSearch for more papers by this authorJing-Jie Tang, Jing-Jie Tang The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, ChinaSearch for more papers by this authorYun-Feng Li, Yun-Feng Li Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, ChinaSearch for more papers by this authorLiguo Wang, Liguo Wang MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, ChinaSearch for more papers by this authorYi-Wen Shao, Yi-Wen Shao The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University Cheeloo Medical College, School of Basic Medical Sciences, Jinan, China The Research Center of Stem Cell and Regenerative Medicine, Shandong University Cheeloo Medical College, School of Basic Medical Sciences, Jinan, ChinaSearch for more papers by this authorXin-Yuan Meng, Xin-Yuan Meng The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University Cheeloo Medical College, School of Basic Medical Sciences, Jinan, China The Research Center of Stem Cell and Regenerative Medicine, Shandong University Cheeloo Medical College, School of Basic Medical Sciences, Jinan, ChinaSearch for more papers by this authorHuili Hu, Huili Hu The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University Cheeloo Medical College, School of Basic Medical Sciences, Jinan, China The Research Center of Stem Cell and Regenerative Medicine, Shandong University Cheeloo Medical College, School of Basic Medical Sciences, Jinan, ChinaSearch for more papers by this authorBao-Liang Song, Corresponding Author Bao-Liang Song blsong@whu.edu.cn orcid.org/0000-0002-6397-5935 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, China Correspondence Bao-Liang Song, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Luojia Hill, Wuhan 430072, China. Email: blsong@whu.edu.cn Yu Rao, MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, 30 Shuangqin Road, Beijing 100084, China. Email: yrao@tsinghua.edu.cn Wei Qi, Gene Editing Center, School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China. Email: qiwei@shanghaitech.edu.cnSearch for more papers by this authorYu Rao, Corresponding Author Yu Rao yrao@tsinghua.edu.cn MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, China Correspondence Bao-Liang Song, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Luojia Hill, Wuhan 430072, China. Email: blsong@whu.edu.cn Yu Rao, MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, 30 Shuangqin Road, Beijing 100084, China. Email: yrao@tsinghua.edu.cn Wei Qi, Gene Editing Center, School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China. Email: qiwei@shanghaitech.edu.cnSearch for more papers by this authorWei Qi, Corresponding Author Wei Qi qiwei@shanghaitech.edu.cn Gene Editing Center, School of Life Science and Technology, ShanghaiTech University, Shanghai, China Correspondence Bao-Liang Song, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Luojia Hill, Wuhan 430072, China. Email: blsong@whu.edu.cn Yu Rao, MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, 30 Shuangqin Road, Beijing 100084, China. Email: yrao@tsinghua.edu.cn Wei Qi, Gene Editing Center, School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China. Email: qiwei@shanghaitech.edu.cnSearch for more papers by this author Shi-You Jiang, Shi-You Jiang Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, China Gene Editing Center, School of Life Science and Technology, ShanghaiTech University, Shanghai, ChinaSearch for more papers by this authorXinglin Yang, Xinglin Yang MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, ChinaSearch for more papers by this authorZimo Yang, Zimo Yang MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, ChinaSearch for more papers by this authorJue-Wan Li, Jue-Wan Li Gene Editing Center, School of Life Science and Technology, ShanghaiTech University, Shanghai, ChinaSearch for more papers by this authorMeng-Qiang Xu, Meng-Qiang Xu Gene Editing Center, School of Life Science and Technology, ShanghaiTech University, Shanghai, ChinaSearch for more papers by this authorYu-Xiu Qu, Yu-Xiu Qu Gene Editing Center, School of Life Science and Technology, ShanghaiTech University, Shanghai, ChinaSearch for more papers by this authorJing-Jie Tang, Jing-Jie Tang The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, ChinaSearch for more papers by this authorYun-Feng Li, Yun-Feng Li Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, ChinaSearch for more papers by this authorLiguo Wang, Liguo Wang MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, ChinaSearch for more papers by this authorYi-Wen Shao, Yi-Wen Shao The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University Cheeloo Medical College, School of Basic Medical Sciences, Jinan, China The Research Center of Stem Cell and Regenerative Medicine, Shandong University Cheeloo Medical College, School of Basic Medical Sciences, Jinan, ChinaSearch for more papers by this authorXin-Yuan Meng, Xin-Yuan Meng The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University Cheeloo Medical College, School of Basic Medical Sciences, Jinan, China The Research Center of Stem Cell and Regenerative Medicine, Shandong University Cheeloo Medical College, School of Basic Medical Sciences, Jinan, ChinaSearch for more papers by this authorHuili Hu, Huili Hu The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University Cheeloo Medical College, School of Basic Medical Sciences, Jinan, China The Research Center of Stem Cell and Regenerative Medicine, Shandong University Cheeloo Medical College, School of Basic Medical Sciences, Jinan, ChinaSearch for more papers by this authorBao-Liang Song, Corresponding Author Bao-Liang Song blsong@whu.edu.cn orcid.org/0000-0002-6397-5935 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, China Correspondence Bao-Liang Song, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Luojia Hill, Wuhan 430072, China. Email: blsong@whu.edu.cn Yu Rao, MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, 30 Shuangqin Road, Beijing 100084, China. Email: yrao@tsinghua.edu.cn Wei Qi, Gene Editing Center, School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China. Email: qiwei@shanghaitech.edu.cnSearch for more papers by this authorYu Rao, Corresponding Author Yu Rao yrao@tsinghua.edu.cn MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, China Correspondence Bao-Liang Song, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Luojia Hill, Wuhan 430072, China. Email: blsong@whu.edu.cn Yu Rao, MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, 30 Shuangqin Road, Beijing 100084, China. Email: yrao@tsinghua.edu.cn Wei Qi, Gene Editing Center, School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China. Email: qiwei@shanghaitech.edu.cnSearch for more papers by this authorWei Qi, Corresponding Author Wei Qi qiwei@shanghaitech.edu.cn Gene Editing Center, School of Life Science and Technology, ShanghaiTech University, Shanghai, China Correspondence Bao-Liang Song, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Luojia Hill, Wuhan 430072, China. Email: blsong@whu.edu.cn Yu Rao, MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, 30 Shuangqin Road, Beijing 100084, China. Email: yrao@tsinghua.edu.cn Wei Qi, Gene Editing Center, School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China. Email: qiwei@shanghaitech.edu.cnSearch for more papers by this author First published: 31 January 2022 https://doi.org/10.1002/hep.32381 Funding information: Supported by grants from the MOST of China (2018YFA0800302, 2019YFA0111400), NNSF of China (91753204, 91857000, 31700711, 32021003, 81573277, 81622042, 81773567, 32122031, and 92068121) and the National Major Scientific and Technological Special Project for “Significant New Drugs Development” (SQ2017ZX095003). B.-L. Song acknowledges support from the Tencent Foundation through the XPLORER PRIZE. Shi-You Jiang, Xinglin Yang and Zimo Yang contributed equally. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat 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. Supporting Information Filename Description hep32381-sup-0001-Supinfo.docxWord 2007 document , 11.3 MB Supplementary Material Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Early ViewOnline Version of Record before inclusion in an issue RelatedInformation