title: Decrease of hepatic stellate cells in rats with enhanced sensitivity to clofibrate-induced hepatocarcinogenesis.
abstract: To examine the possible involvement of nonparenchymal cells in the development of preneoplastic hepatic lesions induced by clofibrate (CF), alterations of these cells were investigated immunohistochemically in glutathione S-transferase M1 gene polymorphic rats (KS and NC types) with different cancer susceptibilities. After CF administration for 8 weeks, α-smooth muscle actin (α-SMA)-positive hepatic stellate cells (HSC) were markedly decreased in sensitive KS-type rats, but not in the NC-type rats. Kupffer cells were decreased with similar extents between them. The sinusoidal endothelial cells were not changed in either type. The other markers for HSC, vimentin and CRBP1, also confirmed the decrease of HSC in the KS type. The decrease of HSC was not observed at 4 weeks of CF administration. Preneoplastic peroxisomal bifunctional enzyme-negative foci were detected in the KS-type rats at 8 weeks of CF administration, but not at 4 weeks. Human HSC were cultured in the presence of clofibric acid and expression of most HSC marker genes, such as vimentin and α-SMA (ACTA2), evaluated by a microarray, was not altered by the treatment, suggesting that HSC loss in the KS-type rats was not due to the direct toxic effect of CF. The expression levels of most HSC marker genes were low in both control and CF-treated rat livers. A possible link between HSC loss and the development of preneoplastic hepatic foci is discussed.
authors.affiliation: Department of Biochemistry and Genome Biology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamana
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimizu
authors.forename: Yang
authors.initials: Y
authors.lastname: Fan
authors.forename: Takuya
authors.initials: T
authors.lastname: Miura
authors.forename: Naoki
authors.initials: N
authors.lastname: Nanashima
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yamada
authors.forename: Kenichi
authors.initials: K
authors.lastname: Hakamada
authors.forename: Shigeki
authors.initials: S
authors.lastname: Tsuchida
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000924:Anticholesteremic Agents / Q000633:toxicity*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D002478:Cells, Cultured; D002994:Clofibrate / Q000633:toxicity*; D004273:DNA, Neoplasm / Q000235:genetics; D020869:Gene Expression Profiling; D005982:Glutathione Transferase / Q000235:genetics; D055166:Hepatic Stellate Cells / Q000187:drug effects*; D006801:Humans; D007124:Immunoenzyme Techniques; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000199:Actins; D000924:Anticholesteremic Agents; D014408:Biomarkers, Tumor; D002994:Clofibrate; D004273:DNA, Neoplasm; D005982:Glutathione Transferase