Abstract
To investigate the role of hepatocyte mitochondrial NDUFA13 loss in the liver fibrogenesis in mice and explore the possible mechanisms. We used liver-specific NDUFA13 heterozygous knockout mouse models (NDUFA13fl/-; Alb-Cre) established previously by intercrossing NDUFA13fl/fl and Alb-Cre mice, with their littermate control NDUFA13fl/fl mice as the control (n=8). The mice were euthanized at the age of 4 weeks and 2 years, and the liver tissues were collected for HE and Masson staining to observe the pathological changes and fibrosis phenotypes. Western blotting was performed to detect the expression of NDUFA13 protein in the liver tissues, and the infiltration of F4/80+ macrophages and the expressions of TGF-β1, TNF-α and IL-1β were analyzed by immunofluorescence assay. The expression levels of α-SMA, matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteases 1 (TIMP-1), collagen-Ⅰ and collagen-Ⅲ were assayed by immunohistochemistry. HE and Masson staining showed obvious inflammatory infiltration but no significant fibrosis in the liver tissues of 4-week-old NDUFA13fl/- mice, but severe liver damage with massive fibrosis was observed in 2-year-old NDUFA13fl/- mice. NDUFA13 expression in 2-year-old NDUFA13fl/- mice markedly decreased compared with that in the control NDUFA13fl/fl mice as shown by Western blotting (P < 0.05). Immunohistochemistry showed obvious infiltration of F4/80+ macrophages in the liver tissue with a large amount of TGF-β1 production (P < 0.05) and TNF-α and IL-1β secretions in NDUFA13fl/- mice (P < 0.05). NDUFA13 knockout obviously promoted α-SMA expression (P < 0.05) and collagen-Ⅰ and collagen-Ⅲ deposition (P < 0.05) while significantly decreased MMP-9 and increased TIMP-1 expression in the liver (P < 0.05). Hepatocytes-specific NDUFA13 deficiency can trigger spontaneous and chronic liver fibrosis phenotypes in mice probably in association with abnormal activation of hepatic stellate cells induced by macrophages and inflammatory factors.
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Schedule a callMore From: Nan fang yi ke da xue xue bao = Journal of Southern Medical University
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