HIGH-LEVELS OF GLUCOSE-6-PHOSPHATASE GENE AND PROTEIN EXPRESSION REFLECT AN ADAPTIVE RESPONSE IN PROLIFERATING LIVER AND DIABETES
HIGH-LEVELS OF GLUCOSE-6-PHOSPHATASE GENE AND PROTEIN EXPRESSION REFLECT AN ADAPTIVE RESPONSE IN PROLIFERATING LIVER AND DIABETES
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DOI：
10.1172/jci117733
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发表时间：
1995-02-01
影响因子：
15.9
通讯作者：
TAUB, R
中科院分区：
文献类型：
--
作者：
HABER, BA;CHIN, S;TAUB, R
肝部分切除后的再生肝是成年动物为数不多的细胞增殖生理学模型之一。在肝脏再生期间，动物能够维持代谢动态平衡，尽管肝脏组织急剧丧失三分之二。在研究调节肝脏再生的分子机制时，我们分离了新的即刻早期基因，这些基因在残肝从正常静止状态过渡到细胞周期的G1期时迅速诱导。编码大鼠葡萄糖-6-磷酸酶(RG6Pase)的基因是最快速和高度诱导的基因之一，我们最初将其命名为RL-1。G6Pase基因在肝切除后30min和36~48h达高峰，与细胞分裂的第一轮和第二轮相关。这一发现与表明G6Pase酶活性在肝脏再生过程中增加的研究是一致的。然而，G6Pase mRNA的增加要剧烈得多，表明它是这种调节的更敏感的指标。G6Pase基因在肝脏中的表达在围产期达到高峰，并在出生后第一个月保持高水平。在BB糖尿病大鼠，G6Pase基因的表达也显著升高，再次高于酶的升高，在这些动物中，其在部分肝切除后的相对诱导被钝化。胰岛素治疗部分肝切除糖尿病动物可下调G6Pase mRNA的表达。使用针对G6Pase的特异性抗体，我们检测到一个36kD的G6Pase蛋白，并且它的水平在再生和糖尿病肝脏中升高。G6Pase mRNA的表达模式似乎反映了伴随糖尿病和肝脏增殖的胰岛素和胰升糖素水平的类似变化。在这些条件下，G6Pase表达的升高表明，在正常和异常生理状态下，G6Pase作为葡萄糖稳态调节因子的重要性。
The regenerating liver after partial hepatectomy is one of the few physiologic models of cellular proliferation in the adult animal. During hepatic regeneration, the animal is able to maintain metabolic homeostasis despite the acute loss of two thirds of hepatic tissue. In examining the molecular mechanisms regulating hepatic regeneration, we isolated novel immediate-early genes that are rapidly induced as the remnant liver undergoes the transition from its normal quiescent state into the G1 phase of the cell cycle. One of the most rapidly and highly induced genes which we initially termed RL-1, encodes rat glucose-6-phosphatase (rG6Pase). G6Pase mRNA peaks at 30 min and 36-48 h after hepatectomy correlating with the first and second rounds of cell division. This finding is compatible with studies that showed that G6Pase enzyme activity increases during liver regeneration. However, the increase in G6Pase mRNA is much more dramatic, indicating that it is a more sensitive indicator of this regulation. G6Pase gene expression peaks in the perinatal time period in the liver and remains elevated during the first month of life. The expression of the G6Pase gene is also dramatically elevated in BB diabetic rats, again higher than the enzyme elevation, and its relative induction after partial hepatectomy is blunted in these animals. Insulin treatment of partially hepatectomized diabetic animals downregulates the expression of G6Pase mRNA. Using specific antibodies against G6Pase, we detect a 36-kD G6Pase protein, and its level is elevated in regenerating and diabetic livers. The pattern of G6Pase mRNA expression appears to reflect similar changes in insulin and glucagon levels which accompany diabetes and hepatic proliferation. The elevation of G6Pase expression in these conditions is indicative of its importance as a regulator of glucose homeostasis in normal and abnormal physiologic states.