Rofe A M, Philcox J C, Coyle P
Division of Clinical Biochemistry, Institute of Medical and Veterinary Science, Adelaide, Australia.
Biochem J. 1996 Mar 15;314 ( Pt 3)(Pt 3):793-7. doi: 10.1042/bj3140793.
Accumulation of hepatic zinc via metallothionein (MT) induction during infection/inflammation is postulated to benefit a range of metabolic processes. The metabolic consequences of two doses of endotoxin (LPS) (1 and 5 mg/kg, intraperitoneally) were examined in normal (MT+/+) and MT-null (MT-/-) mice (all results means =/- S.E.M., n=6). At 16 h after 1 mg/kg LPS, hypozincaemia was pronounced in the MT+/+ mice (4.4+/-0.2 microM), concomitant with a 36% increase in hepatic Zn and a > 10-fold increase in hepatic MT. Plasma Zn (16.6+/-0.7 microM) and total hepatic Zn were unchanged in MT -/- mice, confirming the importance of MT in altering plasma and hepatic Zn during inflammation. Plasma iron was lower in LPS-treated MT-/- mice, whereas plasma copper increased to a similar extent in both groups of mice. Plasma fibrinogen more than doubled, and was similar in both groups of mice, which questions the importance of MT in acute-phase protein synthesis. Blood and liver glucose concentrations were not significantly different between groups before or after LPS, whereas blood and liver lactate concentrations were significantly lower (31% and 24% respectively) in MT-/- mice after LPS. At 16 h after 5 mg/kg LPS, plasma Zn was decreased even further in MT+/+ mice (2.6+/-0.3 microM), but remained unchanged in MT-/- mice at concentrations significantly above those in 16-h fasted MT-/- mice (15.8+/-0.5 versus 11.3+/-0.3 microM). Total liver Zn was 17% lower than fasting values in MT-/- mice, in contrast with 32% higher in MT+/+ mice. Synthesis of MT (in MT+/+ mice) and fibrinogen in all mice was not further enhanced by the higher LPS dose. Blood glucose was significantly decreased by 18% in MT+/+ mice and by 38% in MT-/- mice after 5 mg/kg LPS. There was a marked 44% decrease in liver glucose in MT-/- mice; that in MT+/+ mice was unchanged from fasting levels, implying a deficit in hepatic gluconeogenesis in LPS-treated MT-/- mice. In the absence of any indication of major hepatotoxicity, the results of this study indicate that energy production, and not acute-phase protein synthesis, may be most influenced by Zn supply during endotoxaemia, suggesting that MT has a role in maintaining hepatic and blood glucose in this metabolic setting.
感染/炎症期间通过诱导金属硫蛋白（MT）积累肝脏锌被认为有益于一系列代谢过程。在正常（MT+/+）和MT基因敲除（MT-/-）小鼠中检测了两剂量内毒素（LPS）（1和5mg/kg，腹腔注射）的代谢后果（所有结果均为平均值±标准误，n = 6）。在1mg/kg LPS注射后16小时，MT+/+小鼠出现明显的低锌血症（4.4±0.2μM），同时肝脏锌增加36%，肝脏MT增加超过十倍。MT-/-小鼠的血浆锌（16.6±0.7μM）和肝脏总锌未发生变化，证实了MT在炎症期间改变血浆和肝脏锌方面的重要性。LPS处理的MT-/-小鼠血浆铁较低，而两组小鼠血浆铜均有相似程度的增加。血浆纤维蛋白原增加了一倍多，两组小鼠相似，这对MT在急性期蛋白合成中的重要性提出了质疑。LPS处理前后两组小鼠的血糖和肝糖浓度无显著差异，而LPS处理后MT-/-小鼠的血乳酸和肝乳酸浓度显著降低（分别为31%和24%）。在5mg/kg LPS注射后16小时，MT+/+小鼠血浆锌进一步降低（2.6±0.3μM），而MT-/-小鼠血浆锌保持不变，其浓度显著高于禁食16小时的MT-/-小鼠（15.8±0.5对11.3±0.3μM）。MT-/-小鼠肝脏总锌比禁食值低17%，而MT+/+小鼠则高32%。较高剂量的LPS并未进一步增强所有小鼠中MT（MT+/+小鼠）和纤维蛋白原的合成。5mg/kg LPS注射后，MT+/+小鼠血糖显著降低18%，MT-/-小鼠降低38%。MT-/-小鼠肝脏葡萄糖显著降低44%；MT+/+小鼠肝脏葡萄糖与禁食水平无变化，这意味着LPS处理的MT-/-小鼠肝糖异生存在缺陷。在没有任何重大肝毒性迹象的情况下，本研究结果表明，内毒素血症期间能量产生而非急性期蛋白合成可能受锌供应的影响最大，这表明MT在这种代谢环境中对维持肝脏和血糖有作用。
