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Induction of a hypermetabolic state in cultured hepatocytes by glucagon and H2O2.
Metabolic Engineering ( IF 8.4 ) Pub Date : 2003-12-04 , DOI: 10.1016/s1096-7176(03)00042-9
Kyongbum Lee 1 , François Berthiaume , Gregory N Stephanopoulos , Martin L Yarmush
Affiliation  

Stress hormones and pro-inflammatory cytokines are putative signals triggering increased energy expenditure or "hypermetabolism" commonly observed in inflammatory states. Cytokines also cause the release of reactive oxidants by immune cells resident in tissues in vivo. Therefore, we hypothesized that oxidative stress plays a role in the induction of hypermetabolism. We examined the effect of glucagon (1.0 nM), a catabolic stress hormone, and the oxidant H(2)O(2) (1.0 mM) on the metabolism of stable hepatocyte cultures for 4 days. Combined H(2)O(2) and glucagon treatment, but not H(2)O(2) or glucagon used alone, increased the hepatocyte oxygen uptake rate 25% above control untreated cells after a lag-time of 72 h. The same treatment also increased the expression of mitochondrial uncoupling protein-2 (UCP2). These effects were significantly inhibited by the antioxidant N-acetylcysteine (5mM) and the pentose phosphate pathway (PPP) inhibitor dehydroepianderosterone (200 microM). Glucagon alone induced urea synthesis and H(2)O(2) alone induced the PPP. These findings show, for the first time, that oxidative stress, in combination with glucagon, increases metabolic energy expenditure in cultured cells, and that this effect may be mediated by UCP-2. Furthermore, the results implicate the PPP in the induction of the hypermetabolic response.

中文翻译:

胰高血糖素和过氧化氢在培养的肝细胞中诱导高代谢状态。

应激激素和促炎细胞因子是推定的信号,可触发增加的能量消耗或在炎症状态下常见的“代谢亢进”。细胞因子还引起体内组织中驻留的免疫细胞释放反应性氧化剂。因此,我们假设氧化应激在过度代谢的诱导中起作用。我们检查了胰高血糖素(1.0 nM),分解代谢应激激素和氧化剂H(2)O(2)(1.0 mM)对稳定肝细胞培养4天代谢的影响。联合H(2)O(2)和胰高血糖素治疗,但不是单独使用H(2)O(2)或胰高血糖素,在72小时的滞后时间后,肝细胞吸氧率比未处理的对照细胞高25%。相同的处理还增加了线粒体解偶联蛋白2(UCP2)的表达。抗氧化剂N-乙酰半胱氨酸(5mM)和戊糖磷酸途径(PPP)抑制剂脱氢表雄甾酮(200 microM)显着抑制了这些作用。单独的胰高血糖素诱导尿素合成,单独的H(2)O(2)诱导PPP。这些发现首次表明,氧化应激与胰高血糖素一起增加了培养细胞的代谢能消耗,并且这种作用可能是由UCP-2介导的。此外,该结果暗示了PPP在高代谢反应的诱导中。增加了培养细胞代谢能量的消耗,并且这种影响可能是由UCP-2介导的。此外,该结果暗示了PPP在高代谢反应的诱导中。增加了培养细胞代谢能量的消耗,并且这种影响可能是由UCP-2介导的。此外,该结果暗示了PPP在高代谢反应的诱导中。
更新日期:2019-11-01
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