Expression of the peripheral-type benzodiazepine receptor and apoptosis induction in hepatic stellate cells.
BACKGROUND AND AIMS: Hepatic stellate cell (HSC) transformation and proliferation play an important role in liver fibrogenesis, and HSC apoptosis may be involved in the termination of this response. METHODS: Expression of the peripheral benzodiazepine receptor ( PBR) and PBR-ligand-induced apoptosis were studied in cultured rat liver HSC. RESULTS: Transformation of HSC led to a transient expression of PBR at the messenger RNA and protein level, which was maximal after about 3 and 7 days of culture, respectively, and declined thereafter. Immunoreactive PBR showed a punctate staining and colocalized with mitochondrial manganese-dependent superoxide dismutase and adenine nucleotide translocator 1. The selective PBR ligands 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK11195) and 4' chlorodiazepam (Ro5-4864), but not the centrally acting benzodiazepine ligand clonazepam, induced dose-dependent apoptosis in HSC. The apoptotic potency of PK11195 paralleled the level of PBR expression. PK11195 induced dephosphorylation of protein kinase B/Akt and Bad and a downregulation of Bcl-2. Collapse of the mitochondrial membrane potential preceeded PBR-ligand-induced apoptosis. No apoptosis was induced by PK11195 in parenchymal cells, despite the presence of PBR, and PK11195 had no effect in these cells on Bad phosphorylation and Bcl-2 expression. CONCLUSIONS: Transformation of HSC leads to a transient expression of PBR and renders the cells sensitive to PBR-ligand-induced apoptosis, involving protein kinase B/Akt and Bad-dependent mechanisms.[1]References
- Expression of the peripheral-type benzodiazepine receptor and apoptosis induction in hepatic stellate cells. Fischer, R., Schmitt, M., Bode, J.G., Häussinger, D. Gastroenterology (2001) [Pubmed]
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