Chan T M, Freedland R A
Proc Soc Exp Biol Med. 1976 Feb;151(2):372-5. doi: 10.3181/00379727-151-39213.
Quinolinic acid (Q.A.) which inhibits gluconeogenesis at the site of phosphoenolpyruvate (PEP) synthesis, reduced the content of PEP while elevating that of aspartate and malate in rat livers perfused with a medium containing 10 mM L-lactate. Glucagon at 10(-9) M did not affect Q.A. inhibition of lactate gluconeogenesis nor the depression of PEP level, but further elevated malate and aspartate accumulation. Exogenous butyrate had the same effect as glucagon on these parameters. Butylmalonate (BM), an inhibitor of mitochondrial malate transport, inhibited lactate and propionate gluconeogenesis to similar extents. The addition of 10(-9) M glucagon had no effect on BM inhibition of lactate gluconeogenesis, but almost completely reversed BM inhibition of propionate gluconeogenesis. These results suggest that glucagon may act on at least two sites, resulting in elevated hepatic gluconeogenesis. First, it may stimulate dicarboxylic acid synthesis (malate and oxaloacetate, specifically) through activation of pyruvate carboxylation. Secondly, it may stimulate synthesis of other dicarboxylic acids (fumarate, for example) by activating certain steps of the tricarboxylic acid cycle. The stimulatory effect of glucagon on gluconeogenesis in the perfused rat liver is well documented (1, 2). Exton et al., who earlier located the site of stimulation between pyruvate and PEP synthesis (3), proposed that glucagon stimulated PEP synthesis in the perfused rat liver (4), while reports from Williamson et al. (5) suggested the pyruvate-carboxylase reaction as the site of glucagon action. Stimulation at sites above PEP formation and of portions of the tricarboxylic acid cycle (4) by glucagon have also been suggested (6). In the present experiments, we have used substrates entering at different parts of the gluconeogenic pathway, and specific inhibitors to further resolve the action of glucagon.
喹啉酸（Q.A.）在磷酸烯醇丙酮酸（PEP）合成部位抑制糖异生，在灌注含10 mM L-乳酸培养基的大鼠肝脏中，降低了PEP含量，同时提高了天冬氨酸和苹果酸的含量。10⁻⁹ M的胰高血糖素不影响Q.A.对乳酸糖异生的抑制作用，也不影响PEP水平的降低，但进一步提高了苹果酸和天冬氨酸的积累。外源性丁酸对这些参数的影响与胰高血糖素相同。线粒体苹果酸转运抑制剂丁基丙二酸（BM）对乳酸和丙酸糖异生的抑制程度相似。添加10⁻⁹ M胰高血糖素对BM抑制乳酸糖异生没有影响，但几乎完全逆转了BM对丙酸糖异生的抑制作用。这些结果表明，胰高血糖素可能作用于至少两个部位，导致肝脏糖异生增加。首先，它可能通过激活丙酮酸羧化作用刺激二羧酸合成（特别是苹果酸和草酰乙酸）。其次，它可能通过激活三羧酸循环的某些步骤刺激其他二羧酸（例如富马酸）的合成。胰高血糖素对灌注大鼠肝脏糖异生的刺激作用已有充分记录（1, 2）。埃克斯顿等人早期确定刺激部位在丙酮酸和PEP合成之间（3），提出胰高血糖素刺激灌注大鼠肝脏中的PEP合成（4），而威廉姆森等人的报告（5）表明丙酮酸羧化酶反应是胰高血糖素作用的部位。也有人提出胰高血糖素对PEP形成以上部位和三羧酸循环部分的刺激作用（4）（6）。在本实验中，我们使用了在糖异生途径不同部位进入的底物，以及特异性抑制剂来进一步解析胰高血糖素的作用。
