INHIBITION OF HEPATIC-GLUCONEOGENESIS BY NITRIC-OXIDE - A COMPARISON WITH ENDOTOXIC-SHOCK
INHIBITION OF HEPATIC-GLUCONEOGENESIS BY NITRIC-OXIDE - A COMPARISON WITH ENDOTOXIC-SHOCK
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DOI：
10.1042/bj2990735
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发表时间：
1994-05-01
影响因子：
4.1
通讯作者：
TITHERADGE, MA
中科院分区：
文献类型：
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作者：
HORTON, RA;CEPPI, ED;TITHERADGE, MA
在NO供体S-亚硝基-N-乙酰青霉胺（SNAP）和3-吗啉代壬亚胺（SIN-1）存在下孵育的离体肝细胞显示出时间和剂量依赖性的对葡萄糖合成的抑制作用，葡萄糖合成以乳酸和丙酮酸为底物，与NO产生相关，但与亚硝酸盐产生无关。SNAP的母体化合物，N-乙酰-DL-青霉胺（NAP），也没有亚硝酸盐或硝酸盐对葡萄糖输出有任何显着的影响，表明抑制是由于在孵育培养基中产生NO。这种效应所需的NO浓度（< 800 nM）在完整组织和体内报告的范围内。SNAP的抑制作用的大小（类似于50%）与用乳酸盐加丙酮酸盐作为底物的大鼠的内毒素处理的抑制作用的大小相当。当SNAP对葡萄糖合成和乳酸加丙酮酸合成从一些不同的底物的影响进行了检查，这表明与内毒素治疗后观察到的大鼠，这表明NO可能是抑制介质的细菌内毒素对肝纤维化的影响。NO供体对通过6-磷酸果糖-1-激酶的通量没有影响，这支持了NO和内毒素抑制血管生成的主要位点位于磷酸烯醇丙酮酸形成水平的概念。
Isolated hepatocytes incubated in the presence of the NO donors S-nitroso-N-acetylpenicillamine (SNAP) and 3-morpholinosydnonimine (SIN-1) displayed a time- and dose-dependent inhibition of glucose synthesis from lactate plus pyruvate as the substrate which correlated with NO production, but not nitrite production. Neither the parent compound of SNAP, N-acetyl-DL-penicillamine (NAP), nor nitrite or nitrate had any significant effect on glucose output, indicating that the inhibition was due to the generation of NO within the incubation medium. The concentrations of NO required for this effect (< 800 nM) are within the range reported to occur in intact tissues and in vivo. The magnitude of the inhibitory effect of SNAP (similar to 50%) was comparable with that of endotoxin treatment of the rat with lactate plus pyruvate as the substrate. When the effect of SNAP on glucose synthesis and lactate plus pyruvate synthesis from a number of different substrates was examined, this showed a pattern comparable with that observed after endotoxin treatment of the rat, suggesting that NO may be the inhibitory mediator of the effects of bacterial endotoxin on hepatic gluconeogenesis. The NO donor had no effect on the flux through 6-phosphofructo-1-kinase, supporting the concept that the primary site of inhibition of gluconeogenesis by both NO and endotoxin resides at the level of phosphoenolpyruvate formation.