Lee K, Berthiaume F, Stephanopoulos G N, Yarmush D M, Yarmush M L
Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School and Shriners Burns Hospital, Boston, Massachusetts 02114, USA.
Metab Eng. 2000 Oct;2(4):312-27. doi: 10.1006/mben.2000.0160.
The hepatic response to severe injury is characterized by a marked upregulation of glucose, fatty acid, and amino acid turnover, which, if persistent, predisposes the patient to progressive organ dysfunction. To study the effect of injury on liver intermediary metabolism, metabolic flux analysis was applied to isolated perfused livers of burned and sham-burned rats. Intracellular fluxes were calculated using metabolite measurements and a stoichiometric balance model. Significant flux increases were found for multiple pathways, including mitochondrial electron transport, the TCA and urea cycles, gluconeogenesis, and pentose phosphate pathway (PPP). The burn-induced increase in gluconeogenesis did not significantly increase glucose output. Instead, glucose-6-phosphate was diverted into the PPP. These changes were paralleled by increases in glucose-6-phosphate dehydrogenase (G6PDH) and glutathione reductase (GR) activities. Given that G6PDH and GR are the most significant NADPH producers and consumers in the liver, respectively, and that GR is responsible for recycling the free radical scavenger glutathione, these data are consistent with the notion that hepatic metabolic changes are in part due to the induction of liver antioxidant defenses.
肝脏对严重损伤的反应特征是葡萄糖、脂肪酸和氨基酸周转显著上调，如果这种情况持续存在，会使患者易发生进行性器官功能障碍。为了研究损伤对肝脏中间代谢的影响，将代谢通量分析应用于烧伤和假烧伤大鼠的离体灌注肝脏。使用代谢物测量和化学计量平衡模型计算细胞内通量。发现多个途径的通量显著增加，包括线粒体电子传递、三羧酸循环和尿素循环、糖异生和磷酸戊糖途径（PPP）。烧伤诱导的糖异生增加并未显著增加葡萄糖输出。相反，6-磷酸葡萄糖被分流到PPP中。这些变化与6-磷酸葡萄糖脱氢酶（G6PDH）和谷胱甘肽还原酶（GR）活性的增加同时出现。鉴于G6PDH和GR分别是肝脏中最重要的NADPH产生者和消费者，并且GR负责循环自由基清除剂谷胱甘肽，这些数据与肝脏代谢变化部分归因于肝脏抗氧化防御诱导的观点一致。
