Targeting Gremlin 1 Prevents Intestinal Fibrosis Progression by Inhibiting the Fatty Acid Oxidation of Fibroblast Cells

Yang Yang; Qi-Shan Zeng; Min Zou; Jian Zeng; Jiao Nie; DongFeng Chen; Hua-Tian Gan

doi:10.3389/fphar.2021.663774

Targeting Gremlin 1 Prevents Intestinal Fibrosis Progression by Inhibiting the Fatty Acid Oxidation of Fibroblast Cells

Front Pharmacol. 2021 Apr 22:12:663774. doi: 10.3389/fphar.2021.663774. eCollection 2021.

Authors

Yang Yang^{1

2

3}, Qi-Shan Zeng^{1

2}, Min Zou^{1

2}, Jian Zeng⁴, Jiao Nie^{2

5}, DongFeng Chen³, Hua-Tian Gan^{1

2

5}

Affiliations

¹ Department of Gastroenterology and the Center of Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China.
² Lab of Inflammatory Bowel Disease, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
³ Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China.
⁴ Department of Gastroenterology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China.
⁵ Department of Geriatrics and National Clinical Research Center for Geriatric, West China Hospital, Sichuan University, Chengdu, China.

Abstract

Intestinal fibrosis is a consequence of continuous inflammatory responses that negatively affect the quality of life of patients. By screening altered proteomic profiles of mouse fibrotic colon tissues, we identified that GREM1 was dramatically upregulated in comparison to that in normal tissues. Functional experiments revealed that GREM1 promoted the proliferation and activation of intestinal fibroblast cells by enhancing fatty acid oxidation. Blocking GREM1 prevented the progression of intestinal fibrosis in vivo. Mechanistic research revealed that GREM1 acted as a ligand for VEGFR2 and triggered downstream MAPK signaling. This facilitated the expression of FAO-related genes, consequently enhancing fatty acid oxidation. Taken together, our data indicated that targeting GREM1 could represent a promising therapeutic approach for the treatment of intestinal fibrosis.

Keywords: VEGFR2; fatty acid oxidation; fibroblast cell; gremlin 1; intestinal fibrosis.