Intrahepatic amino acid and glucose metabolism in a D-galactosamine-induced rat liver failure model
Intrahepatic amino acid and glucose metabolism in a D-galactosamine-induced rat liver failure model
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DOI：
10.1053/jhep.2001.26515
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发表时间：
2001-08-01
期刊：
影响因子：
13.5
通讯作者：
Yarmush, ML
中科院分区：
文献类型：
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作者：
Arai, K;Lee, K;Yarmush, ML
更好地了解暴发性肝衰竭（FHF）影响的肝脏代谢途径将有助于开发针对FHF的营养支持和其他非手术治疗方法。我们使用了一个孤立的灌注肝脏系统，结合肝脏中间代谢的质量平衡模型，生成了FHF患者肝脏代谢变化的综合地图。为了诱导FHF，大鼠禁食36小时，在此期间注射2 d -半乳糖胺。然后用含有3% wt/vol牛血清白蛋白和95% o / 2/5% CO2氧合的氨基酸补充Eagle最小必需培养基经门静脉灌注肝脏60分钟。对照大鼠在灌注前禁食36小时，无其他处理。与正常禁食的大鼠肝脏相比，FHF大鼠肝脏表现出氨基酸摄取减少，糖异生向糖酵解转变，尿素合成减少，但氨消耗没有变化。质量平衡分析表明，由于过敏导致进入三羧酸循环的氨基酸减少，肝脏葡萄糖合成受到抑制。此外，FHF抑制肝内天冬氨酸合成，导致尿素循环通量减少50%。外源精氨酸转化为鸟氨酸合成尿素的方法不变。通过谷氨酸合成谷氨酰胺和谷氨酸转化为a-酮戊二酸的减少，定量地维持了氨的去除。肝脏代谢的质量平衡分析将有助于表征FHF期间的变化，并阐明营养补充剂和其他治疗对肝功能的影响。
A better understanding of the hepatic metabolic pathways affected by fulminant hepatic failure (FHF) would help develop nutritional support and other nonsurgical medical therapies for FHF. We used an isolated perfused liver system in combination with a mass-balance model of hepatic intermediary metabolism to generate a comprehensive map of metabolic alterations in the liver in FHF. To induce FHF, rats were fasted for 36 hours, during which they received 2 D-galactosamine injections. The livers were then perfused for 60 minutes via the portal vein with amino acid-supplemented Eagle minimal essential medium containing 3% wt/vol bovine serum albumin and oxygenated with 95% O-2/5% CO2- Control rats were fasted for 36 hours with no other treatment before perfusion. FHF rat livers exhibited reduced amino acid uptake, a switch from gluconeogenesis to glycolysis, and a decrease in urea synthesis, but no change in ammonia consumption compared with normal fasted rat livers. Mass-balance analysis showed that hepatic glucose synthesis was inhibited as a result of a reduction in amino acid entry into the tricarboxylic acid cycle by anaplerosis. Furthermore, FHF inhibited intrahepatic aspartate synthesis, which resulted in a 50% reduction in urea cycle flux. Urea synthesis by conversion of exogenous arginine to ornithine was unchanged. Ammonia removal was quantitatively maintained by glutamine synthesis from glutamate and a decrease in the conversion of glutamate to a-ketoglutarate. Mass-balance analysis of hepatic metabolism will be useful in characterizing changes during FHF, and in elucidating the effects of nutritional supplements and other treatments on hepatic function.