Ontology highlight
ABSTRACT: 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.
INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase
SUBMITTER: Li Ke
PROVIDER: MTBLS5005 | MetaboLights | 2023-04-13
REPOSITORIES: MetaboLights
Items per page: 5 1 - 5 of 13 |
Qu Pengxiang P Rom Oren O Li Ke K Jia Linying L Gao Xiaojing X Liu Zhipeng Z Ding Shusi S Zhao Mingming M Wang Huiqing H Chen Shuangshuang S Xiong Xuelian X Zhao Ying Y Xue Chao C Zhao Yang Y Chu Chengshuang C Wen Bo B Finney Alexandra C AC Zheng Zuowen Z Cao Wenbin W Zhao Jinpeng J Bai Liang L Zhao Sihai S Sun Duxin D Zeng Rong R Lin Jiandie J Liu Wanqing W Zheng Lemin L Zhang Jifeng J Liu Enqi E Chen Y Eugene YE
Cell metabolism 20230410 5
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 fibr ...[more]