Constitutively active PDX1 induced efficient insulin production in adult murine liver
Constitutively active PDX1 induced efficient insulin production in adult murine liver
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DOI：
10.1016/j.bbrc.2004.11.047
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发表时间：
2005-01-14
影响因子：
3.1
通讯作者：
Oka, Y
中科院分区：
文献类型：
--
作者：
Imai, J;Katagiri, H;Oka, Y
为了在肝脏中产生胰岛素产生细胞，制备含有PDX 1的组成型活性突变体（PDX 1-VP 16）的重组腺病毒，并静脉内给予链脲佐菌素（STZ）治疗的糖尿病小鼠，所述PDX 1的组成型活性突变体被设计成在不需要蛋白质伴侣的情况下激活靶基因。将该效果与施用野生型PDX 1（wt-PDX 1）腺病毒的效果进行比较。以2 × 10（8）pfu的剂量给予这些腺病毒，在肝脏中诱导了相似水平的PDX 1蛋白表达。虽然wt-PDX 1表达对血糖水平的影响很小，但用PDX 1-VP 16腺病毒治疗可有效诱导肝细胞中的胰岛素产生，从而逆转STZ诱导的高血糖症。当肝脏中检测不到外源性PDX 1-VP 16蛋白表达时，该作用持续至第40天。内源性PDX 1蛋白在肝脏中表达，这可能是持续作用的机制。另一方面，在肝脏中的胰岛素产生细胞中观察到白蛋白和转铁蛋白表达，表明肝细胞功能得以保留。因此，PDX活性突变体在肝脏中的瞬时表达诱导了持续的PDX 1和胰岛素表达，而没有肝细胞功能的丧失。(C)2004年爱思唯尔公司All rights reserved.
To generate insulin-producing cells in the liver, recombinant adenovirus containing a constitutively active mutant of PDX1 (PDX1-VP16), designed to activate target genes without the need for protein partners, was prepared and administered intravenously to streptozotocin (STZ)-treated diabetic mice. The effects were compared with those of administering wild-type PDX1 (wt-PDX1) adenovirus. Administration of these adenoviruses at 2 x 10(8) pfu induced similar levels of PDX1 protein expression in the liver. While wt-PDX1 expression exerted small effects on blood glucose levels, treatment with PDX1-VP16 adenovirus efficiently induced insulin production in hepatocytes, resulting in reversal of STZ-induced hyperglycemia. The effects were sustained through day 40 when exogenous PDX1-VP16 protein expression was undetectable in the liver. Endogenous PDX1 protein came to be expressed in the liver, which is likely to be the mechanism underlying the sustained effects. On the other hand, albumin and transferrin expressions were observed in insulin-producing cells in the liver, suggesting preservation of hepatocytic functions. Thus, transient expression of an active mutant of PDX in the liver induced sustained PDX1 and insulin expressions without loss of hepatocytic function. (C) 2004 Elsevier Inc. All rights reserved.