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Nuclear Corepressor Is Required for Inhibition of Phosphoenolpyruvate Carboxykinase Expression by Tumor Necrosis Factor-

Department of Endocrinology (J.Ya., J.W.), The First-Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China; and Pennington Biomedical Research Center (Z.G., G.Y., Q.H., J.Ye), Louisiana State University System, Baton Rouge, Louisiana 70808

Address all correspondence and reprint requests to either: J. Weng, Department of Endocrinology, The First-Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China. E-mail: wjianp{at}mail.sysu.edu.cn; or J. Ye, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, Louisiana 70808. E-mail: yej{at}pbrc.edu.

Inhibition of phosphoenolpyruvate carboxykinase (PEPCK) by TNF- contributes to the pathogenesis of hypoglycemia in endotoxin shock. In this study, the molecular mechanism underlying the inhibition was investigated in hepatoma cells (rat H4IIE and human HepG2). PEPCK expression was induced by cAMP, and the induction was reduced by TNF- at protein and mRNA levels in H4IIE cells. The inhibition was observed in the PEPCK gene promoter in a PEPCK-luciferase reporter. Activation of nuclear factor B (NF-B) pathway was required for the transcriptional inhibition of PEPCK gene. Degradation of NF-B inhibitor (IB) and p65 nuclear translocation were involved in the inhibition. An interaction of histone deacetylase 3 (HDAC3) and silencing mediator for retinoic acid receptor and thyroid hormone receptor (SMRT) with the PEPCK gene promoter was induced by TNF- and observed in a chromatin immunoprecipitation assay. The TNF-induced inhibition was blocked by HDAC inhibitor or HDAC3 knockdown. The blocking effect was also observed in knockdown of corepressor SMRT. Point mutation suggests that cAMP response element (CRE) is required for TNF-induced inhibition of the PEPCK gene promoter. Phosphorylation of cAMP response element-binding protein at Ser133 and expression of peroxisome proliferator-activated receptor- coactivator 1 were not changed by TNF- in H4IIE cells. The transcriptional activity of CRE-binding protein was inhibited by TNF- in a CRE-luciferase reporter. The data suggests that the nuclear corepressor proteins of HDAC3 and SMRT mediate TNF inhibition of PEPCK transcription. The inhibition mechanism is related to activation of NF-B and inhibition of CRE-binding protein activity by the corepressor. These data suggest a novel activity of nuclear corepressor in the regulation of PEPCK expression by TNF-.

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Coregulators:   HDAC3  |  NCOR  |  SMRT