Sarraf C E, Horgan M, Edwards R J, Alison M R
Department of Histopathology, RPMS, Hammersmith Hospital, London, UK.
Int J Exp Pathol. 1997 Feb;78(1):49-56. doi: 10.1046/j.1365-2613.1997.d01-238.x.
Fas is a cell surface receptor that mediates apoptosis, and Fas mRNA has been demonstrated in hepatocytes. MRL/MP-lpr/lpr mice carry the mutated lymphoproliferation-associated gene, lpr, that codes for truncated Fas protein, resulting in reduced apoptotic potential in some circumstances. Phenobarbital treatment of experimental animals induces cytochrome P450 enzymes, and thus acts as a growth stimulus to the liver with both hyperplasia and hypertrophy; cessation results in reversion of liver to normal size with apoptosis playing a role. This study has determined the respective contributions of atrophy and apoptosis to this involution in Fas-defective and normal-FAs bearing animals. Between the first day and the fifth day after phenobarbital cessation, the weights of both Fas-defective (lpr/lpr) livers and control (lpr/+) livers reduced. Hepatocyte hypertrophy gradually reverted in both categories of mouse and this was the greater contribution to reduction in liver size. In lpr/lpr animals, there was a consistent level of apoptosis which remained relatively constant, while numbers of apoptotic cells in control livers increased over the period. This investigation has shown that in liver, a mechanism to execute apoptosis is operative even in Fas-defective mice, but it is not sensitive to signals activated by the removal of the growth stimulus. This is in contrast to mice which can mount a Fas-mediated response; thus a separate apoptotic pathway is indicated.
Fas是一种介导细胞凋亡的细胞表面受体，并且已在肝细胞中证实有Fas信使核糖核酸（mRNA）。MRL/MP-lpr/lpr小鼠携带与淋巴细胞增殖相关的突变基因lpr，该基因编码截短的Fas蛋白，导致在某些情况下细胞凋亡潜力降低。对实验动物进行苯巴比妥治疗可诱导细胞色素P450酶，因此对肝脏起到生长刺激作用，会导致肝脏增生和肥大；停止治疗后，肝脏会恢复到正常大小，细胞凋亡在其中发挥作用。本研究确定了在Fas缺陷型和正常Fas的动物中，萎缩和细胞凋亡对这种退化的各自贡献。在停止使用苯巴比妥后的第一天到第五天之间，Fas缺陷型（lpr/lpr）肝脏和对照（lpr/+）肝脏的重量均减轻。两类小鼠的肝细胞肥大逐渐恢复，这对肝脏体积减小的贡献更大。在lpr/lpr动物中，细胞凋亡水平保持一致且相对稳定，而对照肝脏中的凋亡细胞数量在此期间增加。这项研究表明，在肝脏中，即使在Fas缺陷型小鼠中，执行细胞凋亡的机制也是有效的，但它对因去除生长刺激而激活的信号不敏感。这与能够产生Fas介导反应的小鼠形成对比；因此表明存在一条独立的细胞凋亡途径。
