DT-109 ameliorates nonalcoholic steatohepatitis in nonhuman primates

Pengxiang Qu¹, Oren Rom², Ke Li³, Linying Jia¹, Xiaojing Gao⁴, Zhipeng Liu⁵, Shusi Ding³, Mingming Zhao⁶, Huiqing Wang⁶, Shuangshuang Chen⁷, Xuelian Xiong⁷, Ying Zhao⁸, Chao Xue⁸, Yang Zhao⁸, Chengshuang Chu⁹, Bo Wen¹⁰, Alexandra C Finney¹¹, Zuowen Zheng¹², Wenbin Cao¹, Jinpeng Zhao¹, Liang Bai¹, Sihai Zhao¹, Duxin Sun¹⁰, Rong Zeng⁴, Jiandie Lin¹³, Wanqing Liu¹⁴, Lemin Zheng¹⁵, Jifeng Zhang¹⁶, Enqi Liu¹⁷, Y Eugene Chen¹⁸

Affiliations

¹ Laboratory Animal Center, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi 710061, China.
² Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI 48109, USA; Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA; Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA; Center for Cardiovascular Diseases and Sciences, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA.
³ Beijing Tiantan Hospital, China National Clinical Research Center for Neurological Diseases, Advanced Innovation Center for Human Brain Protection, Capital Medical University, 6 Tiantan Xili, Chongwen District, Beijing 100050, China.
⁴ Key Laboratory of Systems Health Science of Zhejiang Province, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; CAS Key Laboratory of Systems Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
⁵ Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
⁶ The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of Ministry of Education, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Health Science Center, Peking University, 38 Xue Yuan Road, Beijing 100191, China.
⁷ Department of Endocrinology and Metabolism, Fudan Institute of Metabolic Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai 200031, China.
⁸ Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI 48109, USA.
⁹ CAS Key Laboratory of Systems Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
¹⁰ Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
¹¹ Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA.
¹² Spring Biological Technology Development Co., Ltd, Fangchenggang, Guangxi 538000, China.
¹³ Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
¹⁴ Department of Pharmaceutical Sciences and Department of Pharmacology, Wayne State University, Detroit, MI 48201, USA.
¹⁵ Beijing Tiantan Hospital, China National Clinical Research Center for Neurological Diseases, Advanced Innovation Center for Human Brain Protection, Capital Medical University, 6 Tiantan Xili, Chongwen District, Beijing 100050, China; The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of Ministry of Education, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Health Science Center, Peking University, 38 Xue Yuan Road, Beijing 100191, China. Electronic address: zhengl@bjmu.edu.cn.
¹⁶ Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI 48109, USA. Electronic address: jifengz@umich.edu.
¹⁷ Laboratory Animal Center, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi 710061, China. Electronic address: liuenqi@mail.xjtu.edu.cn.
¹⁸ Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI 48109, USA. Electronic address: echenum@umich.edu.

PMID: 37040763
DOI: 10.1016/j.cmet.2023.03.013

Free article

DT-109 ameliorates nonalcoholic steatohepatitis in nonhuman primates

Pengxiang Qu et al. Cell Metab. 2023.

Free article

. 2023 May 2;35(5):742-757.e10.

doi: 10.1016/j.cmet.2023.03.013. Epub 2023 Apr 10.

Authors

Affiliations

¹ Laboratory Animal Center, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi 710061, China.
² Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI 48109, USA; Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA; Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA; Center for Cardiovascular Diseases and Sciences, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA.
³ Beijing Tiantan Hospital, China National Clinical Research Center for Neurological Diseases, Advanced Innovation Center for Human Brain Protection, Capital Medical University, 6 Tiantan Xili, Chongwen District, Beijing 100050, China.
⁴ Key Laboratory of Systems Health Science of Zhejiang Province, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; CAS Key Laboratory of Systems Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
⁵ Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
⁶ The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of Ministry of Education, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Health Science Center, Peking University, 38 Xue Yuan Road, Beijing 100191, China.
⁷ Department of Endocrinology and Metabolism, Fudan Institute of Metabolic Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai 200031, China.
⁸ Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI 48109, USA.
⁹ CAS Key Laboratory of Systems Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
¹⁰ Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
¹¹ Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA.
¹² Spring Biological Technology Development Co., Ltd, Fangchenggang, Guangxi 538000, China.
¹³ Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
¹⁴ Department of Pharmaceutical Sciences and Department of Pharmacology, Wayne State University, Detroit, MI 48201, USA.
¹⁵ Beijing Tiantan Hospital, China National Clinical Research Center for Neurological Diseases, Advanced Innovation Center for Human Brain Protection, Capital Medical University, 6 Tiantan Xili, Chongwen District, Beijing 100050, China; The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of Ministry of Education, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Health Science Center, Peking University, 38 Xue Yuan Road, Beijing 100191, China. Electronic address: zhengl@bjmu.edu.cn.
¹⁶ Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI 48109, USA. Electronic address: jifengz@umich.edu.
¹⁷ Laboratory Animal Center, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi 710061, China. Electronic address: liuenqi@mail.xjtu.edu.cn.
¹⁸ Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI 48109, USA. Electronic address: echenum@umich.edu.

PMID: 37040763
DOI: 10.1016/j.cmet.2023.03.013

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.

Keywords: DT-109; amino acids; bile acids; gut microbiota; nonalcoholic steatohepatitis; nonhuman primates; therapeutic.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests O.R., Y.Z., J.Z., and Y.E.C. have filed a patent application (tri-peptides and treatment of metabolic, cardiovascular, and inflammatory disorders: PCT/US2019/046052). Y.E.C. is the founder of Diapin Therapeutics, which licensed DT-109 from the University of Michigan to develop DT-109 for clinical applications. Diapin Therapeutics provided DT-109 for this study.

Comment in

Tripeptide treats NASH in non-human primates.
Crunkhorn S. Crunkhorn S. Nat Rev Drug Discov. 2023 Jun;22(6):448. doi: 10.1038/d41573-023-00070-4. Nat Rev Drug Discov. 2023. PMID: 37142700 No abstract available.

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

LinkOut - more resources

Full Text Sources
- Elsevier Science
Other Literature Sources
- The Lens - Patent Citations Database
Medical
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

DT-109 ameliorates nonalcoholic steatohepatitis in nonhuman primates

Affiliations

DT-109 ameliorates nonalcoholic steatohepatitis in nonhuman primates

Authors

Affiliations

Abstract

Conflict of interest statement

Comment in

Publication types

MeSH terms

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical