C‐terminal binding protein 1 (CTBP1) and the redox control the PEPCK‐C gene transcription

Transcription of the hepatic gene for the cytosolic isoform of phosphoenolpyruvate carboxykinase (GTP) (PEPCK‐C) (EC 4.1.1.32) is acutely regulated by a number of transcription factors and co‐regulators in response to stimuli such as hormones and nutrients. Since the cellular redox status controls the function of various transcription factors, we investigated the possibility of transcription factor‐mediated redox control of the PEPCK‐C gene transcription. When the cellular NAD + /NADH ratio was decreased after treating cells with ethanol, the expression of PEPCK‐C was attenuated, while cells treated with pyruvate, which increases the cellular NAD + /NADH ratio, showed an elevated expression of the gene for PEPCK‐C. Cobalt chloride, which induces hypoxia in cells and decreases the cellular NAD + /NADH ratio, also inhibited transcription from the PEPCK‐C gene promoter in HepG2 cells. The C‐terminal binding protein 1 (CTBP1), which is activated by NADH, has been implicated as a redox sensor in cells. We investigated its effect on transcription from the PEPCK‐C gene promoter. CTBP1 markedly repressed transcription of PEPCK‐C gene promoter in the presence of the catalytic subunit of protein kinase A. We conclude that a decrease in NAD + /NADH ratio activates CTBP1, which in turn represses PEPCK‐C gene transcription. Supported by grants DK058620 and DK025541 from the NIH.