title: Depletion of activated hepatic stellate cell correlates with severe liver damage and abnormal liver regeneration in acetaminophen-induced liver injury.
abstract: Hepatic stellate cells (HSCs) are important part of the local 'stem cell niche' for hepatic progenitor cells (HPCs) and hepatocytes. However, it is unclear as to whether the products of activated HSCs are required to attenuate hepatocyte injury, enhance liver regeneration, or both. In this study, we performed 'loss of function' studies by depleting activated HSCs with gliotoxin. It was demonstrated that a significantly severe liver damage and declined survival rate were correlated with depletion of activated HSCs. Furthermore, diminishing HSC activation resulted in a 3-fold increase in hepatocyte apoptosis and a 66% decrease in the number of proliferating hepatocytes. This was accompanied by a dramatic decrease in the expression levels of five genes known to be up-regulated during hepatocyte replication. In particular, it was found that depletion of activated HSCs inhibited oval cell reaction that was confirmed by decreased numbers of Pank-positive cells around the portal tracts and lowered gene expression level of cytokeratin 19 (CK19) in gliotoxin-treated liver. These data provide clear evidence that the activated HSCs are involved in both hepatocyte death and proliferation of hepatocytes and HPCs in acetaminophen (APAP)-induced acute liver injury.
authors.affiliation: Department of General Surgery, Institute of General Surgery, Zhongshan Hospital, Shanghai Medical College of Fudan University, China.
authors.forename: Kuntang
authors.initials: K
authors.lastname: Shen
authors.forename: Wenju
authors.initials: W
authors.lastname: Chang
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Gao
authors.forename: Hongshan
authors.initials: H
authors.lastname: Wang
authors.forename: Weixin
authors.initials: W
authors.lastname: Niu
authors.forename: Lujun
authors.initials: L
authors.lastname: Song
authors.forename: Xinyu
authors.initials: X
authors.lastname: Qin
mesh_terms: D000082:Acetaminophen / Q000633:toxicity; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000401:mortality / Q000503:physiopathology*; D015870:Gene Expression / Q000187:drug effects; D005912:Gliotoxin / Q000494:pharmacology; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology; D053208:Kaplan-Meier Estimate; D053539:Keratin-19 / Q000235:genetics / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008115:Liver Regeneration; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate
chemical_list: D007166:Immunosuppressive Agents; D053539:Keratin-19; D000082:Acetaminophen; D005912:Gliotoxin; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase