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To investigate the significance and involvement of heparanase in liver fibrosis, we compared the susceptibility of wild-type (WT) and heparanase-overexpressing transgenic (Hpa-tg) mice to carbon tetrachloride (CCL4)-induced fibrosis. In comparison with WT mice, Hpa-tg mice displayed a severe degree of tissue damage and fibrosis, including higher necrotic tendency and intensified expression of smooth muscle actin. While damage to the WT liver started to recover after the acute phase, damage to the Hpa-tg liver was persistent. Recovery was attributed, in part, to heparanase-stimulated autophagic activity in response to CCL4, leading to increased apoptosis and necrosis. The total number of stellate cells was significantly higher in the Hpa-tg than the WT liver, likely contributing to the increased amounts of lipid droplets and smooth muscle actin. Our results support the notion that heparanase enhances inflammatory responses, and hence may serve as a target for the treatment of liver damage and fibrosis.<\/jats:p>","DOI":"10.3390\/cells11132035","type":"journal-article","created":{"date-parts":[[2022,6,27]],"date-time":"2022-06-27T22:31:14Z","timestamp":1656369074000},"page":"2035","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Heparanase Expression Propagates Liver Damage in CCL4-Induced Mouse Model"],"prefix":"10.3390","volume":"11","author":[{"given":"Xiaowen","family":"Cheng","sequence":"first","affiliation":[{"name":"SciLifeLab Uppsala, The Biomedical Center, Department of Medical Biochemistry and Microbiology, University of Uppsala, 75237 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Jia","sequence":"additional","affiliation":[{"name":"SciLifeLab Uppsala, The Biomedical Center, Department of Medical Biochemistry and Microbiology, University of Uppsala, 75237 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianji","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Chemistry and Analytical Science, National Institute of Metrology, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Uppsala, 75237 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Israel","family":"Vlodavsky","sequence":"additional","affiliation":[{"name":"Cancer and Vascular Biology Research Center Rappaport, Faculty of Medicine, Technion 31096, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-ping","family":"Li","sequence":"additional","affiliation":[{"name":"SciLifeLab Uppsala, The Biomedical Center, Department of Medical Biochemistry and Microbiology, University of Uppsala, 75237 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/nri3623","article-title":"Liver fibrosis and repair: Immune regulation of wound healing in a solid organ","volume":"14","author":"Pellicoro","year":"2014","journal-title":"Nat. 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