DT-109 ameliorates nonalcoholic steatohepatitis in nonhuman primates.
DT-109 ameliorates nonalcoholic steatohepatitis in nonhuman primates.
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DOI：
10.1016/j.cmet.2023.03.013
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发表时间：
2023-04
期刊：
影响因子：
29
通讯作者：
P. Qu;O. Rom;Ke Li;Linying Jia;Xiaojing Gao;Zhipeng Liu;Shusi Ding;Mingming Zhao;Huiqing Wang;Shuangshuang Chen;X. Xiong;Ying Zhao;Chao Xue;Yang Zhao;Chengshuang Chu;Bo Wen;Alexandra C. Finney;Zuowen Zheng;Wenbin Cao;Jinpeng Zhao;Liang Bai;Sihai Zhao;Duxin Sun;R. Zeng;Jiandie D. Lin;Wanqing Liu;Lemin Zheng;Jifeng Zhang;Enqi Liu;Y. E. Chen
中科院分区：
文献类型：
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作者：
P. Qu;O. Rom;Ke Li;Linying Jia;Xiaojing Gao;Zhipeng Liu;Shusi Ding;Mingming Zhao;Huiqing Wang;Shuangshuang Chen;X. Xiong;Ying Zhao;Chao Xue;Yang Zhao;Chengshuang Chu;Bo Wen;Alexandra C. Finney;Zuowen Zheng;Wenbin Cao;Jinpeng Zhao;Liang Bai;Sihai Zhao;Duxin Sun;R. Zeng;Jiandie D. Lin;Wanqing Liu;Lemin Zheng;Jifeng Zhang;Enqi Liu;Y. E. Chen
非酒精性脂肪性肝炎(NASH)患病率正在上升，没有药物治疗获批。NASH药物开发的一个主要障碍是临床前研究对安全/有效临床结果的可转译性差，最近的失败突出了确定新的靶向途径的必要性。失调的甘氨酸代谢已成为NASH的致病因素和治疗靶点。在这里，我们报道了三肽DT-109 （Gly-Gly-Leu）剂量依赖性减轻小鼠脂肪性肝炎和纤维化。为了提高成功翻译的可能性，我们开发了一个非人类灵长类动物模型，在组织学和转录上模仿人类NASH。应用转录组学、蛋白质组学、代谢组学和宏基因组学相结合的多组学方法，我们发现DT-109不仅通过刺激脂肪酸降解和谷胱甘肽形成（如在小鼠中发现的），还通过调节微生物胆汁酸代谢，逆转非人类灵长类动物的肝脂肪变性和防止纤维化进展。我们的研究描述了一个高度可翻译的NASH模型，并强调了对DT-109进行临床评估的必要性。
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.