SOD3 deficiency induces liver fibrosis by promoting hepatic stellate cell activation and epithelial–mesenchymal transition

• Published in: Journal of cellular physiology 2021-06, Vol.236 (6), p.4313-4329
• Main Authors: Sun, Yu‐Ling, Bai, Tao, Zhou, Lin, Zhu, Rong‐Tao, Wang, Wei‐Jie, Liang, Ruo‐Peng, Li, Jian, Zhang, Chi‐Xian, Gou, Jian‐Jun
• Format: Article
• Language: English
• Subjects: Actin; Adenosine kinase; Adenosine monophosphate; AMP; AMP-Activated Protein Kinases - metabolism; Animals; Antioxidants; Bile; Carbon Tetrachloride; Cell activation; Cells, Cultured; Chemical and Drug Induced Liver Injury - enzymology; Chemical and Drug Induced Liver Injury - etiology; Chemical and Drug Induced Liver Injury - genetics; Chemical and Drug Induced Liver Injury - pathology; Collagen; Collagen (type I); Collagen Type I - metabolism; Depletion; Epithelial-Mesenchymal Transition; Fibrosis; Growth factors; hepatic stellate cell activation; Hepatic Stellate Cells - enzymology; Hepatic Stellate Cells - pathology; Hepatocytes; Kinases; Liver; Liver - enzymology; Liver - pathology; Liver Cirrhosis, Experimental - chemically induced; Liver Cirrhosis, Experimental - enzymology; Liver Cirrhosis, Experimental - genetics; Liver Cirrhosis, Experimental - pathology; liver fibrosis; Male; Mesenchyme; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscles; Pathogenesis; Protein kinase; Signal Transduction; SIRT1; SIRT1 protein; Sirtuin 1 - metabolism; Smooth muscle; SOD3; Superoxide dismutase; Superoxide Dismutase - deficiency; Superoxide Dismutase - genetics; Transforming growth factor-b1; Vimentin
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.30174

Hepatic stellate cell (HSC) activation plays an important role in the pathogenesis of liver fibrosis, and epithelial–mesenchymal transition (EMT) is suggested to potentially promote HSC activation. Superoxide dismutase 3 (SOD3) is an extracellular antioxidant defense against oxidative damage. Here, we found downregulation of SOD3 in a mouse model of liver fibrosis induced by carbon tetrachloride (CCl4). SOD3 deficiency induced spontaneous liver injury and fibrosis with increased collagen deposition, and further aggravated CCl4‐induced liver injury in mice. Depletion of SOD3 enhanced HSC activation marked by increased α‐smooth muscle actin and subsequent collagen synthesis primarily collagen type I in vivo, and promoted transforming growth factor‐β1 (TGF‐β1)‐induced HSC activation in vitro. SOD3 deficiency accelerated EMT process in the liver and TGF‐β1‐induced EMT of AML12 hepatocytes, as evidenced by loss of E‐cadherin and gain of N‐cadherin and vimentin. Notably, SOD3 expression and its pro‐fibrogenic effect were positively associated with sirtuin 1 (SIRT1) expression. SOD3 deficiency inhibited adenosine monophosphate‐activated protein kinase (AMPK) signaling to downregulate SIRT1 expression and thus involving in liver fibrosis. Enforced expression of SIRT1 inhibited SOD3 deficiency‐induced HSC activation and EMT, whereas depletion of SIRT1 counteracted the inhibitory effect of SOD3 in vitro. These findings demonstrate that SOD3 deficiency contributes to liver fibrogenesis by promoting HSC activation and EMT process, and suggest a possibility that SOD3 may function through modulating SIRT1 via the AMPK pathway in liver fibrosis. Superoxide dismutase 3 (SOD3) deficiency promotes hepatic stellate cell activation and epithelial–mesenchymal transition in vivo and in vitro, which contributes to liver fibrogenesis. Notably, SOD3 expression and its pro‐fibrogenic effect were positively associated with sirtuin 1 expression via regulation of adenosine monophosphate‐activated protein kinase signaling.