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Influences of diabetes mellitus and insulin resistance on hepatic synthesis of serum paraoxonase 1

糖尿病和胰岛素抵抗对肝脏合成血清对氧磷酶1的影响

基本信息

批准号：
16590887
负责人：
IKEDA Yukio
金额：
$ 2.3万
依托单位：
Kochi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590887/
关键词：
paraoxonase PON1 diabetes mellitus insulin resistance sand rat パラキオソナーゼ

项目摘要

1.Effects of glucose and insulin on transcription of human serum paraoxonase 1 (PON1) gene : D-glucose, but not L-glucose or mannitol, significantly enhanced PON1 transcriptional activity in both HepG2 and Huh7 human hepatoma cell lines (reporter gene assay). Insulin also enhanced the transcriptional activity, but its effect was minor. 2.Effects of glucose and insulin on PON1 mRNA and protein expressions : D-glucose, but not insulin, enhanced PON1 mRNA expression in Huh7 cells (RT-PCR). D-glucose also increased PON1 protein expression in both Huh7 cells and human primary hepatocytes (western blotting). 3.Mechanism of glucose-induced transactivation of PON1 gene : Bisindolylmaleimide, a protein kinase C (PKC) inhibitor, partially inhibited D-glucose-induced transactivation of PON1 gene, and mythramycin, an inhibitor of transcriptional factor Sp1, completely abrogated the transactivation. Deletion analyses revealed that the promoter sequence (-269/-97) containing Sp1 binding sites was crucial for the transactivation. 4.Hepatic PON1 expression in diabetic Psammomys obesus (sand rat) : Significantly increased PON1 expression in the liver was detected in the diabetic (hyperinsulinemic, hyperglycemic) animals as compared with the control (normoinsulinemic, normoglycemic) animals. The prediabetic (hperinsulinemic, normoglycemic) animals showed no significant change in hepatic PON1 expression. 5.Conclusion : Hyperglycemia, but not hyperinsulinemia, increases hepatic PON1 synthesis. Our data suggest that activated diacylglycerol-PKC pathway under hyperglycemic condition promotes PON1 transcription through Sp1 activation.

1.葡萄糖和胰岛素对人血清对氧磷酶1（PON 1）基因转录的影响：D-葡萄糖，而不是L-葡萄糖或甘露醇，显着增强PON 1在HepG 2和Huh 7人肝癌细胞系的转录活性（报告基因测定）。胰岛素也能增强转录活性，但作用较小。2.葡萄糖和胰岛素对PON 1 mRNA和蛋白表达的影响：D-葡萄糖，而不是胰岛素，能增强Huh 7细胞PON 1 mRNA的表达（RT-PCR）。D-葡萄糖还增加了Huh 7细胞和人原代肝细胞中的PON 1蛋白表达（蛋白质印迹法）。3.葡萄糖诱导的PON 1基因转录激活机制：蛋白激酶C（PKC）抑制剂双吲哚马来酰亚胺部分抑制D-葡萄糖诱导的PON 1基因转录激活，转录因子Sp1抑制剂美拉霉素完全抑制D-葡萄糖诱导的PON 1基因转录激活。缺失分析表明，含有Sp1结合位点的启动子序列（-269/-97）对转录激活至关重要。4.糖尿病沙鼠（沙鼠）肝脏PON 1表达：与对照（正常胰岛素血症、正常血糖）动物相比，糖尿病（高胰岛素血症、高血糖）动物肝脏中PON 1表达显着增加。糖尿病前期（高胰岛素血症，血糖正常）动物的肝脏PON 1表达没有显着变化。5.结论：高胰岛素血症，而不是高胰岛素血症，增加肝脏PON 1的合成。我们的数据表明，在高血糖条件下激活的二酰甘油-PKC通路促进PON 1的转录通过Sp1激活。