Reducing Nogo-B Improves Hepatic Fibrosis by Inhibiting BACe1-Mediated Autophagy
10.1007/s13770-024-00641-5
- Author:
LiLi GAO
1
;
YingJie ZHUANG
;
ZhengYi LIU
Author Information
1. Department of Gastroenterology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, No.28, Fuxing Road, Haidian District, Beijing City 100853, China
- Publication Type:ORIGINAL ARTICLE
- From:
Tissue Engineering and Regenerative Medicine
2024;21(5):777-789
- CountryRepublic of Korea
- Language:EN
-
Abstract:
BACKGROUND:Hepatic fibrosis (HF) is a histopathological change in the process of long-term liver injury caused by cytokine secretion and internal environment disturbance, resulting in excessive liver repair and fiber scar. Nogo-B protein is widely distributed in peripheral tissues and organs and can regulate the migration of endothelial cells by activating TGFb1 in vascular remodeling after injury. Nogo-B has been shown to promote organ fibrosis. This study was to determine the role of Nogo-B in HF.
METHODS:An HF model was built by intraperitoneal injections with 20% carbon tetrachloride. Localization of Nogo-B was detected by FISH. The interaction between Nogo-B and BACE1 was confirmed by Co-IP. Autophagy flux was analyzed using tandem mRFP-GFP-LC3 fluorescence microscopy, electron microscopy, and western blotting. Detection of serum AST and ALT and H&E staining were utilized to detect the degree of liver injury. The HF was evaluated by Masson trichromatic staining. RT-qPCR, western blotting, and immunofluorescence were employed to detect relevant indicators.
RESULTS:Reducing Nogo-B suppressed AST and ALT levels, the accumulation of collagen I and a-SMA, and expressions of pro-fibrotic genes in mouse liver. BACE1 was a potential downstream target of Nogo-B. Nogo-B was upregulated in TGF-b1-activated hepatic stellate cells (HSCs). Knocking down Nogo-B caused the downregulation of profibrotic genes and inhibited viability of HSCs. Nogo-B knockdown prevented CCL4-induced fibrosis, accompanied by downregulation of extracellular matrix. Nogo-B inhibited HSC autophagy and increased lipid accumulation. BACE1 knockdown inhibited HSC autophagy and activation in LX-2 cells.
CONCLUSION:Nogo-B knockdown prevents HF by directly inhibiting BACe1-mediated autophagy.
