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

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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.