Lyonnet S, Coupé C, Girard J, Kahn A, Munnich A
Institut National de la Santé et de la Recherche Médicale U129, Unité de Génétique et Pathologie Moléculaires, Paris, France.
J Clin Invest. 1988 Jun;81(6):1682-9. doi: 10.1172/JCI113506.
Glucagon and its second messenger, cAMP, are known to rapidly block expression of the L-type pyruvate kinase gene and to stimulate expression of phosphoenolpyruvate (PEP) carboxykinase gene in the liver in vivo. The respective roles, however, of hyperglucagonemia, insulinopenia, and carbohydrate deprivation in the inhibition of L-type pyruvate kinase gene expression during fasting are poorly understood. In addition, the long-term effects of physiological hyperglucagonemia on expression of the two genes are not known. In this study, we investigate the effects of long-term physiological hyperglucagonemia and insulinopenia induced by suckling (which provides a high-fat, low-carbohydrate diet) on expression of the two genes in the liver of normal newborn rats. We show that transcription of the L-type pyruvate kinase gene is inhibited at birth and remains low during the whole suckling period, whereas transcription of the PEP carboxykinase gene is maximal in the neonate, and then decreases despite very high levels of plasma glucagon during suckling. In contrast to the adult, however, in which L-type pyruvate kinase gene expression in the liver is blocked by cAMP and stimulated by carbohydrates, the regulation of L-type pyruvate kinase gene expression in the newborn undergoes a developmental maturation: the inhibitory effect of glucagon is never complete in developing rat liver and the stimulatory effect of glucose could not be detected during suckling, due to either hyperglucagonemia, immaturity of the gene regulatory system, or both.
已知胰高血糖素及其第二信使环磷酸腺苷（cAMP）可在体内迅速阻断肝脏中L型丙酮酸激酶基因的表达，并刺激磷酸烯醇式丙酮酸（PEP）羧激酶基因的表达。然而，在禁食期间，高胰高血糖素血症、胰岛素缺乏和碳水化合物缺乏在抑制L型丙酮酸激酶基因表达中各自所起的作用却鲜为人知。此外，生理性高胰高血糖素血症对这两个基因表达的长期影响也不清楚。在本研究中，我们探究了由哺乳诱导的长期生理性高胰高血糖素血症和胰岛素缺乏（哺乳提供高脂肪、低碳水化合物饮食）对正常新生大鼠肝脏中这两个基因表达的影响。我们发现，L型丙酮酸激酶基因的转录在出生时即受到抑制，并且在整个哺乳期间一直保持在低水平，而PEP羧激酶基因的转录在新生儿期最高，然后尽管哺乳期间血浆胰高血糖素水平很高，但仍会下降。然而，与成年动物不同，成年动物肝脏中L型丙酮酸激酶基因表达受cAMP阻断并受碳水化合物刺激，新生动物中L型丙酮酸激酶基因表达的调控经历了一个发育成熟过程：在发育中的大鼠肝脏中，胰高血糖素的抑制作用从未完全实现，并且由于高胰高血糖素血症、基因调节系统不成熟或两者兼而有之，在哺乳期间未检测到葡萄糖的刺激作用。
