Fischer R, Schmitt M, Bode J G, Häussinger D
Medizinische Universitätsklinik, Heinrich Heine Universität Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
Gastroenterology. 2001 Apr;120(5):1212-26. doi: 10.1053/gast.2001.23260.
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.
Expression of the peripheral benzodiazepine receptor (PBR) and PBR-ligand-induced apoptosis were studied in cultured rat liver HSC.
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.
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.
肝星状细胞（HSC）的转化和增殖在肝纤维化形成过程中起重要作用，而HSC凋亡可能参与该反应的终止。
在培养的大鼠肝HSC中研究外周苯二氮䓬受体（PBR）的表达及PBR配体诱导的凋亡。
HSC的转化导致PBR在信使核糖核酸和蛋白质水平短暂表达，分别在培养约3天和7天后达到最大值，随后下降。免疫反应性PBR呈点状染色，并与线粒体锰依赖性超氧化物歧化酶和腺嘌呤核苷酸转位体1共定位。选择性PBR配体1-(2-氯苯基)-N-甲基-N-(1-甲基丙基)-3-异喹啉甲酰胺（PK11195）和4'-氯地西泮（Ro5-4864），而非中枢作用的苯二氮䓬配体氯硝西泮，在HSC中诱导剂量依赖性凋亡。PK11195的凋亡效力与PBR表达水平平行。PK11195诱导蛋白激酶B/Akt和Bad去磷酸化以及Bcl-2下调。线粒体膜电位崩溃先于PBR配体诱导的凋亡。尽管存在PBR，但PK11195在实质细胞中未诱导凋亡，且PK11195对这些细胞的Bad磷酸化和Bcl-2表达无影响。
HSC的转化导致PBR短暂表达，并使细胞对PBR配体诱导的凋亡敏感，涉及蛋白激酶B/Akt和Bad依赖性机制。
