SIRT4 protects against intestinal fibrosis by facilitating GLS1 degradation

In this study, fibroblasts isolated from biopsies of stenotic ileal mucosa in CD patients were analyzed to identify the most down-regulated protein among SIRT1-7, and SIRT4 was found to be the most affected. Moreover, in in vivo and in vitro models of intestinal fibrosis, SIRT4 expression was significantly decreased in a TGF-β dependent manner, and its decrease was negatively associated with disease severity. SIRT4 impeded ECM deposition by inhibiting glutaminolysis, but not glycolysis, and α-ketoglutarate (α-KG) was identified as the key metabolite. Specifically, SIRT4 hinders SIRT5's stabilizing interaction with glutaminase 1 (GLS1), thereby facilitating the degradation of GLS1. KDM6, rather than KDM4, is a potential mediator for α-KG-induced transcription of ECM components, and SIRT4 enhances the enrichment of H3K27 on their promotors and enhancers. These findings indicate that the activation of TGF-β signals decreases the expression of SIRT4 in intestinal fibrosis, and SIRT4 can facilitate GLS1 degradation, thereby resisting glutaminolysis and alleviating intestinal fibrosis, providing a novel therapeutic target for intestinal fibrosis.PMID:37541633 | DOI:10.1016/j.matbio.2023.08.001
Source: Matrix Biology - Category: Molecular Biology Authors: Source Type: research