Pilkis S J, Claus T H, el-Maghrabi M R
Department of Physiology and Biophysics, State University of New York, Stony Brook 11794.
Adv Second Messenger Phosphoprotein Res. 1988;22:175-91.
Cyclic AMP plays a major, if not primary, role in the regulation of hepatic gluconeogenesis. The cyclic nucleotide acts on two levels. First, cAMP levels determine the phosphorylation state of key regulatory enzymes including pyruvate kinase and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Regulation of cAMP levels by glucagon, insulin, and catecholamines accounts in large part for minute-to-minute hormonal control of pathway flux in fed animals and during the transition from fed to starved; second, cAMP plays a key role in regulation of gene transcription of phosphoenolpyruvate carboxykinase, pyruvate kinase, glucokinase, and probably 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Cyclic AMP acts to induce synthesis of mRNA for phosphoenolpyruvate carboxykinase and probably fructose 1, 6-bisphosphatase while it suppresses transcription of the genes for pyruvate kinase and glucokinase. Its role in the regulation of gene transcription of the bifunctional enzyme and 6-phosphofructo 1-kinase remains to be defined. Insulin is the most important hormone for restraining the level of cAMP. Insulin acts to oppose the acute actions of cAMP on enzyme phosphorylation, presumably by activating a phosphodiesterase and thereby lowering cAMP levels. Insulin also opposes the action of hormones (alpha-adrenergic agonists, angiotensin, vasopressin) that act in liver via cAMP-independent phosphorylation. However, in the systems in which this has been studied, the cAMP-independent effects on gluconeogenic/glycolytic pathway flux are small in comparison to cAMP-dependent regulation. Insulin also opposes the action of cAMP on gene transcription by an as yet unknown mechanism. This effect does not appear to involve changes in the level of cAMP because the hormone also acts in cultured cells when added alone or in the presence of dexamethasone. The ability of insulin to lower hepatic cAMP levels and to modulate gene expression are important because restoration of acute regulatory hormone responsiveness to starved or diabetic animals could not occur if insulin were unable to lower cAMP levels and be the dominant factor in modulating the gene expression of these key regulatory enzymes. Clearly, the hepatic gluconeogenic/glycolytic pathway undergoes a complex but extremely well-integrated regulation by hormones that accounts in large part for the major role the organ plays in the control of glucose homeostasis.
环磷酸腺苷（cAMP）在肝脏糖异生的调节中起着主要作用，即便不是首要作用。这种环核苷酸在两个层面发挥作用。首先，cAMP水平决定关键调节酶的磷酸化状态，这些酶包括丙酮酸激酶和6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶。胰高血糖素、胰岛素和儿茶酚胺对cAMP水平的调节在很大程度上解释了进食动物以及从进食状态转变为饥饿状态期间，该途径通量的每分钟激素控制情况；其次，cAMP在磷酸烯醇式丙酮酸羧激酶、丙酮酸激酶、葡萄糖激酶以及可能的6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶的基因转录调节中起关键作用。环磷酸腺苷可诱导磷酸烯醇式丙酮酸羧激酶以及可能的果糖1,6-二磷酸酶的mRNA合成，同时抑制丙酮酸激酶和葡萄糖激酶基因的转录。其在双功能酶和6-磷酸果糖-1-激酶基因转录调节中的作用尚待明确。胰岛素是抑制cAMP水平的最重要激素。胰岛素的作用是对抗cAMP对酶磷酸化的急性作用，可能是通过激活磷酸二酯酶从而降低cAMP水平来实现。胰岛素还对抗通过不依赖cAMP的磷酸化作用于肝脏的激素（α-肾上腺素能激动剂、血管紧张素、血管加压素）的作用。然而，在已研究的这些系统中，与依赖cAMP的调节相比，不依赖cAMP对糖异生/糖酵解途径通量的影响较小。胰岛素还通过一种未知机制对抗cAMP对基因转录的作用。这种作用似乎不涉及cAMP水平的变化，因为该激素单独添加或在存在地塞米松的情况下添加到培养细胞中时也能发挥作用。胰岛素降低肝脏cAMP水平和调节基因表达的能力很重要，因为如果胰岛素无法降低cAMP水平且不能成为调节这些关键调节酶基因表达的主导因素，饥饿或糖尿病动物对急性调节激素的反应性就无法恢复。显然，肝脏糖异生/糖酵解途径受到激素的复杂但极其协调的调节，这在很大程度上解释了该器官在控制葡萄糖稳态中所起的主要作用。
