Reducing Nogo-B Improves Hepatic Fibrosis by Inhibiting BACe1-Mediated Autophagy

• DOI: 10.1007/s13770-024-00641-5
• Publication Date: 2024-04-17T13:04:57Z
• Authors: LiLi Gao; YingJie Zhuang; ZhengYi Liu
• Keywords: Liver Cirrhosis; Male; Mice, Inbred C57BL; Mice; Liver; Nogo Proteins; Autophagy; Hepatic Stellate Cells; Animals; Aspartic Acid Endopeptidases; Humans; Amyloid Precursor Protein Secretases; Carbon Tetrachloride

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 TGF-β1 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.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.Reducing Nogo-B suppressed AST and ALT levels, the accumulation of collagen I and α-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-β1-activated hepatic stellate cells (HSCs). Knocking down Nogo-B caused the downregulation of pro-fibrotic 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.Nogo-B knockdown prevents HF by directly inhibiting BACe1-mediated autophagy.