小柯机器人

美国密歇根大学Y. Eugene Chen，Jifeng Zhang，西安交通大学Enqi Liu和首都医科大学Lemin Zheng团队共同合作，近期取得重要工作进展。他们研究发现DT-109可改善非人灵长类动物的非酒精性脂肪性肝炎。相关研究成果2023年4月10日在线发表于《细胞—代谢》杂志上。

据介绍，非酒精性脂肪性肝炎（NASH）的患病率正在上升，但尚未批准药物治疗。NASH药物开发的一个主要障碍是临床前研究转化为安全、有效临床结果的能力差，而最近的失败突出表明需要确定新的靶向途径。甘氨酸代谢失调已成为NASH的致病因素和治疗靶点。

研究人员报道，三肽DT-109（Gly-Gly-Leu）可以剂量依赖性地减轻小鼠的脂肪性肝炎和纤维化。为了提高转化成功的概率，研究人员开发了一种非人类灵长类动物模型，该模型在组织学和转录学上模拟了人类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，研究人员发现DT-109不仅通过刺激小鼠体内的脂肪酸降解和谷胱甘肽形成，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并防止纤维化进展。

总之，这一研究描述了一个高度可转化的NASH模型，并强调了对DT-109进行临床评估的必要性。

附：英文原文

Title: DT-109 ameliorates nonalcoholic steatohepatitis in nonhuman primates

Author: Pengxiang Qu, Oren Rom, Ke Li, Linying Jia, Xiaojing Gao, Zhipeng Liu, Shusi Ding, Mingming Zhao, Huiqing Wang, Shuangshuang Chen, Xuelian 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, Rong Zeng, Jiandie Lin, Wanqing Liu, Lemin Zheng, Jifeng Zhang, Enqi Liu, Y. Eugene Chen

Issue&Volume: 2023-04-10

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.

DOI: 10.1016/j.cmet.2023.03.013

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00091-8

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