激素调节肝脏糖代谢的机制。

J H Exton
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引用次数: 161

摘要

肝脏碳水化合物代谢的急性激素调节主要涉及细胞内cAMP和Ca2+水平的变化。肾上腺素通过β 2-肾上腺素能受体和胰高血糖素激活肝质膜中的腺苷酸环化酶,其机制涉及刺激酶的鸟嘌呤核苷酸结合蛋白。由此产生的cAMP积累导致cAMP依赖性蛋白激酶的激活,进而使许多参与糖原代谢、糖异生和糖酵解调节的细胞内酶磷酸化。它们是(1)磷酸化酶b激酶,它被激活,进而磷酸化并激活磷酸化酶,磷酸化酶是糖原分解的限速酶;(2)糖原合成酶,它灭活并控制糖原合成的速率;(3)丙酮酸激酶,失活,是糖酵解的重要调节酶;(4) 6-磷酸果糖-2-激酶/果糖2,6-双磷酸酶双功能酶,其磷酸化导致果糖2,6- p2的形成减少,果糖2,6- p2是6-磷酸果糖-1-激酶的激活剂和果糖1,6-双磷酸酶的抑制剂,两者都是糖酵解和糖异生的重要调节酶。胰高血糖素和β -肾上腺素能激动剂除了通过刺激糖原分解和糖异生以及抑制糖原合成和糖酵解而快速增加肝脏葡萄糖输出外,这些药物还通过改变糖异生/糖酵解和氨基酸代谢的某些酶的合成而对糖异生产生长期的刺激作用。例如,p -烯醇丙酮酸羧激酶是通过camp依赖性蛋白激酶介导的转录水平效应诱导的。酪氨酸氨基转移酶、丝氨酸脱水酶、色氨酸加氧酶和葡萄糖激酶也受cAMP调控,部分调控在特定信使RNA合成水平上。交感神经系统及其神经体液激动剂肾上腺素和去甲肾上腺素也能通过α - 1-肾上腺素能受体迅速改变肝糖原代谢和糖异生。对这些激动剂的主要反应是磷酸二酯酶介导的质膜多磷酸肌醇磷脂酰肌醇4,5- p2分解为肌醇1,4,5- p3和1,2-二酰基甘油。这涉及一种鸟嘌呤核苷酸结合蛋白,它与参与腺苷酸环化酶调节的蛋白不同。肌醇1,4,5- p3通过从内质网释放Ca2+作为Ca2+动员的细胞内信使。(摘要删节为400字)
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Mechanisms of hormonal regulation of hepatic glucose metabolism.

Acute hormonal regulation of liver carbohydrate metabolism mainly involves changes in the cytosolic levels of cAMP and Ca2+. Epinephrine, acting through beta 2-adrenergic receptors, and glucagon activate adenylate cyclase in the liver plasma membrane through a mechanism involving a guanine nucleotide-binding protein that is stimulatory to the enzyme. The resulting accumulation of cAMP leads to activation of cAMP-dependent protein kinase, which, in turn, phosphorylates many intracellular enzymes involved in the regulation of glycogen metabolism, gluconeogenesis, and glycolysis. These are (1) phosphorylase b kinase, which is activated and, in turn, phosphorylates and activates phosphorylase, the rate-limiting enzyme for glycogen breakdown; (2) glycogen synthase, which is inactivated and is rate-controlling for glycogen synthesis; (3) pyruvate kinase, which is inactivated and is an important regulatory enzyme for glycolysis; and (4) the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase bifunctional enzyme, phosphorylation of which leads to decreased formation of fructose 2,6-P2, which is an activator of 6-phosphofructo-1-kinase and an inhibitor of fructose 1,6-bisphosphatase, both of which are important regulatory enzymes for glycolysis and gluconeogenesis. In addition to rapid effects of glucagon and beta-adrenergic agonists to increase hepatic glucose output by stimulating glycogenolysis and gluconeogenesis and inhibiting glycogen synthesis and glycolysis, these agents produce longer-term stimulatory effects on gluconeogenesis through altered synthesis of certain enzymes of gluconeogenesis/glycolysis and amino acid metabolism. For example, P-enolpyruvate carboxykinase is induced through an effect at the level of transcription mediated by cAMP-dependent protein kinase. Tyrosine amino-transferase, serine dehydratase, tryptophan oxygenase, and glucokinase are also regulated by cAMP, in part at the level of specific messenger RNA synthesis. The sympathetic nervous system and its neurohumoral agonists epinephrine and norepinephrine also rapidly alter hepatic glycogen metabolism and gluconeogenesis acting through alpha 1-adrenergic receptors. The primary response to these agonists is the phosphodiesterase-mediated breakdown of the plasma membrane polyphosphoinositide phosphatidylinositol 4,5-P2 to inositol 1,4,5-P3 and 1,2-diacylglycerol. This involves a guanine nucleotide-binding protein that is different from those involved in the regulation of adenylate cyclase. Inositol 1,4,5-P3 acts as an intracellular messenger for Ca2+ mobilization by releasing Ca2+ from the endoplasmic reticulum.(ABSTRACT TRUNCATED AT 400 WORDS)

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