Dual activation of GCGR/GLP1R signaling ameliorates intestinal fibrosis via metabolic regulation of histone H3K9 lactylation in epithelial cells
Intestinal fibrosis is a significant clinical challenge in inflammatory bowel diseases, but no effective anti-fibrotic therapy is currently available. Glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP1R) are both peptide hormone receptors involved in energy metabolism of epithelial cells. However, their role in intestinal fibrosis and the underlying mechanisms remain largely unexplored. Herein GCGR and GLP1R were found to be reduced in the stenotic ileum of patients with Crohn's disease as well as in the fibrotic colon of mice with chronic colitis. The downregulation of GCGR and GLP1R led to the accumulation of the metabolic byproduct lactate, resulting in histone H3K9 lactylation and exacerbated intestinal fibrosis through epithelial-to-mesenchymal transition (EMT). Dual activating GCGR and GLP1R by peptide 1907B reduced the H3K9 lactylation in epithelial cells and ameliorated intestinal fibrosis <i>in vivo</i>. We uncovered the role of GCGR/GLP1R in regulating EMT involved in intestinal fibrosis <i>via</i> histone lactylation. Simultaneously activating GCGR/GLP1R with the novel dual agonist peptide 1907B holds promise as a treatment strategy for alleviating intestinal fibrosis.
Authors
- Qinglin Tang (ORCID: https://orcid.org/0000-0003-1815-9645)
- Han Liu (ORCID: https://orcid.org/0000-0002-0022-1861)
- Zihan Shi
- Florian Rieder (ORCID: https://orcid.org/0000-0002-9087-1568)
- Xianxing Jiang (ORCID: https://orcid.org/0000-0002-7508-2368)
- Qian Zhao (ORCID: https://orcid.org/0000-0001-8103-8251)
- Yujie Hong
- Longyuan Zhou (ORCID: https://orcid.org/0000-0002-3057-2566)
- Xianggui Wang (ORCID: https://orcid.org/0000-0003-0955-2461)
- Jiaxin Wang (ORCID: https://orcid.org/0000-0003-4808-5085)
- Rui Wang (ORCID: https://orcid.org/0000-0003-3825-3620)
- Qi Liu (ORCID: https://orcid.org/0000-0002-4569-5980)
- Xiaoqian Li (ORCID: https://orcid.org/0000-0001-6676-735X)
- Hui Chen (ORCID: https://orcid.org/0009-0007-8937-5317)
- Yao Zhang (ORCID: https://orcid.org/0000-0002-8180-7361)
- Qingjie Zeng (ORCID: https://orcid.org/0000-0001-7172-0353)
- Minhu Chen (ORCID: https://orcid.org/0000-0001-8181-0846)
- Ren Mao
- Jiale Dong
- Baili Chen (ORCID: https://orcid.org/0000-0003-1755-5806)
Institutions
- Cleveland Clinic (US)
- Sun Yat-sen University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Ruijin Hospital (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- Lanzhou University (CN)
Publication Details
- Journal
- Acta Pharmaceutica Sinica B
- Published
- 2024-11-27
- DOI
- https://doi.org/10.1016/j.apsb.2024.11.017
- Citations
- 15
- Primary Topic
- Digestive system and related health
- Type
- article
- Field-Weighted Citation Impact
- 8.25
Funders
- Lanzhou University
- National Natural Science Foundation of China