Chronic liver disease in murine hereditary tyrosinemia type 1 induces resistance to cell death
Chronic liver disease in murine hereditary tyrosinemia type 1 induces resistance to cell death
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DOI：
10.1002/hep.20077
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发表时间：
2004-02-01
期刊：
影响因子：
13.5
通讯作者：
Grompe, M
中科院分区：
文献类型：
--
作者：
Vogel, A;van den Berg, IET;Grompe, M
采用小鼠遗传性1型酪氨酸血症（HT1）模型，分析慢性肝病与体内细胞程序性死亡的关系。在健康富马酰乙酸水解酶缺陷小鼠（Fah(-1-)）中，通过药物2-（2-硝基-4-三氟甲基苯甲酰）-1,3-环己二酮（NTBC）保护肝脏免受损伤，酪氨酸代谢物均质酸（HGA）引起肝细胞快速死亡。相比之下，所有小鼠在相同致死剂量的HGA下都存活了下来，如果它们先前存在由NTBC戒断引起的肝损伤。同样，肝损伤的Fah（-1-）动物也对Fas配体Jo-2诱导的细胞凋亡和对乙酰氨基酚（APAP）诱导的坏死样细胞死亡具有抗性。分子研究显示肝细胞中抗凋亡热休克蛋白（Hsp） 27、32、70和c-Jun显著上调；有压力的老鼠。此外，p38和Jun n -末端激酶（JNK）应激激活激酶途径在细胞死亡抵抗性肝脏中明显受损。总之，这些结果提供了证据，证明慢性肝病可以矛盾地导致体内细胞死亡抵抗。应激诱导的细胞死亡程序失败可能导致受损细胞的积累，从而增加HT1和其他慢性肝脏疾病的癌症风险。
The murine model of hereditary tyrosinemia type 1 (HT1) was used to analyze the relationship between chronic liver disease and programmed cell death in vivo. In healthy fumarylacetoacetate hydrolase deficient mice (Fah(-1-)), protected from liver injury by the drug 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), the tyrosine metabolite homogentisic acid (HGA) caused rapid hepatocyte death. In contrast, all mice survived the same otherwise lethal dose of HGA if they had preexisting liver damage induced by NTBC withdrawal. Similarly, Fah(-1-) animals with liver injury were also resistant to apoptosis induced by the Fas ligand Jo-2 and to necrosis-like cell death induced by acetaminophen (APAP). Molecular studies revealed a marked up-regulation of the antiapoptotic heat shock proteins (Hsp) 27, 32, and 70 and of c-Jun in hepatocytes; of stressed mice. In addition, the p38 and Jun N-terminal kinase (JNK) stress-activated kinase pathways were markedly impaired in the cell-death resistant liver. In conclusion, these results provide evidence that chronic liver disease can paradoxically result in cell death resistance in vivo. Stress-induced failure of cell death programs may lead to an accumulation of damaged cells and therefore enhance the risk for cancer as observed in HT1 and other chronic liver diseases.