DT-109 ameliorates nonalcoholic steatohepatitis in nonhuman primates

• Published in: Cell metabolism Vol. 35; no. 5; pp. 742 - 757.e10
• Main Authors: Qu, Pengxiang, Rom, Oren, Li, Ke, Jia, Linying, Gao, Xiaojing, Liu, Zhipeng, Ding, Shusi, Zhao, Mingming, Wang, Huiqing, Chen, Shuangshuang, Xiong, Xuelian, Zhao, Ying, Xue, Chao, Zhao, Yang, Chu, Chengshuang, Wen, Bo, Finney, Alexandra C., Zheng, Zuowen, Cao, Wenbin, Zhao, Jinpeng, Bai, Liang, Zhao, Sihai, Sun, Duxin, Zeng, Rong, Lin, Jiandie, Liu, Wanqing, Zheng, Lemin, Zhang, Jifeng, Liu, Enqi, Chen, Y. Eugene
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.05.2023
• Subjects: amino acids; Animals; bile acids; DT-109; Fibrosis; gut microbiota; Humans; Lipid Metabolism; Liver - metabolism; Mice; Non-alcoholic Fatty Liver Disease - metabolism; nonalcoholic steatohepatitis; nonhuman primates; Primates; therapeutic; nonalcoholic steatohepatitis; therapeutic; DT-109; bile acids; amino acids; nonhuman primates; gut microbiota
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2023.03.013

Nonalcoholic steatohepatitis (NASH) prevalence is rising with no pharmacotherapy approved. A major hurdle in NASH drug development is the poor translatability of preclinical studies to safe/effective clinical outcomes, and recent failures highlight a need to identify new targetable pathways. Dysregulated glycine metabolism has emerged as a causative factor and therapeutic target in NASH. Here, we report that the tripeptide DT-109 (Gly-Gly-Leu) dose-dependently attenuates steatohepatitis and fibrosis in mice. To enhance the probability of successful translation, we developed a nonhuman primate model that histologically and transcriptionally mimics human NASH. Applying a multiomics approach combining transcriptomics, proteomics, metabolomics, and metagenomics, we found that DT-109 reverses hepatic steatosis and prevents fibrosis progression in nonhuman primates, not only by stimulating fatty acid degradation and glutathione formation, as found in mice, but also by modulating microbial bile acid metabolism. Our studies describe a highly translatable NASH model and highlight the need for clinical evaluation of DT-109. [Display omitted] •A nonhuman primate NASH model is established to mimic human disease•DT-109 attenuates steatohepatitis, inflammation, and fibrosis in NASH•DT-109 regulates FA degradation, GSH formation, and microbial BA metabolism•This study emphasizes the importance of evaluating DT-109 in clinical settings Qu et al. have discovered that DT-109, a tripeptide (Gly-Gly-Leu), reduces steatohepatitis, inflammation, and fibrosis in nonhuman primates with NASH. This suggests the importance of testing DT-109 in clinical trials as a potential treatment option for NASH.