Repression of Glucagon Gene Transcription by Peroxisome Proliferator-activated Receptor γ through Inhibition of Pax6 Transcriptional Activity*
Repression of Glucagon Gene Transcription by Peroxisome Proliferator-activated Receptor γ through Inhibition of Pax6 Transcriptional Activity*
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过氧化物酶体增殖物激活受体 γ 通过抑制 Pax6 转录活性来抑制胰高血糖素基因转录*
DOI：
10.1074/jbc.m109718200
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
W. Knepel
中科院分区：
文献类型：
--
作者：
S. Schinner;C. Dellas;M. Schröder;C. Heinlein;Chawnshang Chang;J. Fischer;W. Knepel
核受体过氧化物酶体增殖物激活受体γ(PPARγ)参与葡萄糖稳态和合成的PPARγ配体，噻唑烷二酮是一类新型抗糖尿病药物，可降低胰岛素抵抗，并作为辅助作用减少肝脏葡萄糖输出。PPARγ在正常的人胰岛α细胞中高表达，PPAR DNA是分泌高血糖素的细胞。这种多肽激素是胰岛素刺激肝脏葡萄糖输出的功能性拮抗剂。因此，我们研究了PPARγ和噻唑烷二酮类化合物对胰升糖素基因转录的影响。将胰升糖素-报告融合基因瞬时导入胰岛细胞系后，当PPARγ共表达时，噻唑烷二酮类化合物可抑制胰升糖素基因转录。它们还减少了初级胰岛中高血糖素的分泌和组织中的高血糖素水平。5‘/3’缺失和内部突变分析表明，胰岛细胞特异性增强子序列(PISCES)位于胰升糖素启动子近端元件G1中，是PPARγ应答所必需的。该序列基序与配对的结构域转录因子Pax6结合。当G1内的双鱼基序突变为Gal4结合位点时，Gal4-Pax6的表达恢复了胰高血糖素启动子的活性和PPAR的γ反应性。在病毒启动子最小的情况下，PPARγ也能抑制GAL4Pax6的转录活性。这些结果表明，PPARγ以配体依赖但不依赖于DNA结合的方式抑制Pax6的转录活性，从而抑制胰高血糖素基因的转录。因此，这些数据将Pax6定义为PPARγ的一个新的功能靶点，并提示抑制胰高血糖素基因的表达可能是噻唑烷二酮改善糖尿病患者血糖控制的多种机制之一。
The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is involved in glucose homeostasis and synthetic PPARγ ligands, the thiazolidinediones, a new class of antidiabetic agents that reduce insulin resistance and, as a secondary effect, reduce hepatic glucose output. PPARγ is highly expressed in normal human pancreatic islet α-cells that produce glucagon. This peptide hormone is a functional antagonist of insulin stimulating hepatic glucose output. Therefore, the effect of PPARγ and thiazolidinediones on glucagon gene transcription was investigated. After transient transfection of a glucagon-reporter fusion gene into a glucagon-producing pancreatic islet cell line, thiazolidinediones inhibited glucagon gene transcription when PPARγ was coexpressed. They also reduced glucagon secretion and glucagon tissue levels in primary pancreatic islets. A 5′/3′-deletion and internal mutation analysis indicated that a pancreatic islet cell-specific enhancer sequence (PISCES) motif within the proximal glucagon promoter element G1 was required for PPARγ responsiveness. This sequence motif binds the paired domain transcription factor Pax6. When the PISCES motif within G1 was mutated into a GAL4 binding site, the expression of GAL4-Pax6 restored glucagon promoter activity and PPARγ responsiveness. GAL4-Pax6 transcriptional activity was inhibited by PPARγ in response to thiazolidinedione treatment also at a minimal viral promoter. These results suggest that PPARγ in a ligand-dependent but DNA binding-independent manner inhibits Pax6 transcriptional activity, resulting in inhibition of glucagon gene transcription. These data thereby define Pax6 as a novel functional target of PPARγ and suggest that inhibition of glucagon gene expression may be among the multiple mechanisms through which thiazolidinediones improve glycemic control in diabetic subjects.
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影响因子：
10.5
作者：
Sander, M;Neubuser, A;German, MS
通讯作者：
German, MS
大鼠核糖体基因的多个功能增强子基序。
影响因子：
4.3
作者：
Jacob,ST;Zhang,J;Garg,LC;Book,CB
通讯作者：
Book,CB
影响因子：
2.7
作者：
S. Nordeen
通讯作者：
S. Nordeen
胰岛特异性胰高血糖素 G3 转录因子识别大鼠生长抑素和胰岛素-I 基因中的控制元件。
DOI：
10.1210/mend-5-10-1457
发表时间：
1991
期刊：
Molecular endocrinology (Baltimore, Md.)
影响因子：
--
作者：
Knepel,W;Vallejo,M;Chafitz,JA;Habener,JF
通讯作者：
Habener,JF
影响因子：
15.9
作者：
Han, KH;Chang, MK;Quehenberger, O
通讯作者：
Quehenberger, O