Skip to main content
 
Notice: Users may be experiencing issues with displaying some pages on stanfordhealthcare.org. We are working closely with our technical teams to resolve the issue as quickly as possible. Thank you for your patience.
Stanford Health Care

ECM1 attenuates hepatic fibrosis by interfering with mediators of latent TGF-ß1 activation.

ECM1 attenuates hepatic fibrosis by interfering with mediators of latent TGF-ß1 activation. Gut Link, F., Li, Y., Zhao, J., Munker, S., Fan, W., Nwosu, Z. C., Yao, Y., Wang, S., Huang, C., Liebe, R., Hammad, S., Liu, H., Shao, C., Gao, C., Sun, B., Török, N. J., Ding, H., Ebert, M. P., Weng, H., Ten Dijke, P., Drasdo, D., Dooley, S., Wang, S. 2024

Abstract

Extracellular matrix protein 1 (ECM1) serves as a gatekeeper of hepatic fibrosis by maintaining transforming growth factor-ß1 (TGF-ß1) in its latent form. ECM1 knockout (KO) causes latent (L) TGF-ß1 activation, resulting in hepatic fibrosis with rapid mortality. In chronic liver disease (CLD), ECM1 decreases with increasing CLD severity. We investigate the regulatory role of ECM1 in TGF-ß1 bioavailability and its impact on CLD progression.RNAseq was performed to analyse hepatic gene expression. Functional assays were performed using hepatic stellate cells (HSCs), Ecm1-KO and Fxr-KO mice, patient liver tissue and computer simulations.Expression of LTGF-ß1 activators, including thrombospondins (TSPs), ADAMTS proteases and matrix metalloproteinases (MMPs), increased along with profibrotic gene expression in liver tissue of Ecm1-KO mice. In HSCs, overexpression of ECM1 prevented LTGF-ß1 activation mediated by TSP-1, ADAMTS1, and MMP-2/9. In vitro interaction assays demonstrated that ECM1 inhibited LTGF-ß1 activation by interacting with TSP-1 and ADAMTS1 via their respective, intrinsic KRFK or KTFR amino acid sequences and by suppressing MMP-2/9 proteolytic activity. In mice, ECM1 overexpression attenuated KRFK-induced LTGF-ß1 activation while KTFR treatment reversed Ecm1-KO-mediated and Fxr-KO-mediated liver injury. In patients with CLD, ECM1 expression was inversely correlated with TSP-1, ADAMTS1, MMP-2/9 expression and LTGF-ß1 activation. And, these results were complemented by a computational compartment model representing the key network of cellular phenotypes and predicted interactions in liver fibrogenesis.Our findings underscore the hepatoprotective effect of ECM1, which interferes with mediators of LTGF-ß1 activation, suggesting ECM1 or its representative peptide as potential antifibrotic therapies in CLD.

View details for DOI 10.1136/gutjnl-2024-333213

View details for PubMedID 39448254