The promoter for the gene encoding the catalytic subunit of rat glucose-6-phosphatase contains two distinct glucose-responsive regions

Kim B. Pedersen, Pili Zhang, Chris Doumen, Marcel Charbonnet, Danhong Lu, Christopher B. Newgard, John W. Haycock, Alex J Lange, Donald K. Scott

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

Glucose homeostasis requires the proper expression and regulation of the catalytic subunit of glucose-6-phosphatase (G-6-Pase), which hydrolyzes glucose 6-phosphate to glucose in glucose-producing tissues. Glucose induces the expression of G-6-Pase at the transcriptional and posttranscriptional levels by unknown mechanisms. To better understand this metabolic regulation, we mapped the cis-regulatory elements conferring glucose responsiveness to the rat G-6-Pase gene promoter in glucose-responsive cell lines. The full-length (-4078/+64) promoter conferred a moderate glucose response to a reporter construct in HL1C rat hepatoma cells, which was dependent on coexpression of glucokinase. The same construct provided a robust glucose response in 832/13 INS-1 rat insulinoma cells, which are not glucogenic. Glucose also strongly increased endogenous G-6-Pase mRNA levels in 832/13 cells and in rat pancreatic islets, although the induced levels from islets were still markedly lower than in untreated primary hepatocytes. A distal promoter region was glucose responsive in 832/13 cells and contained a carbohydrate response element with two E-boxes separated by five base pairs. Carbohydrate response element-binding protein bound this region in a glucose-dependent manner in situ. A second, proximal promoter region was glucose responsive in both 832/13 and HL1C cells, with a hepatocyte nuclear factor 1 binding site and two cAMP response elements required for glucose responsiveness. Expression of dominant-negative versions of both cAMP response element-binding protein and CAAT/enhancer-binding protein blocked the glucose response of the proximal region in a dose-dependent manner. We conclude that multiple, distinct cisregulatory promoter elements are involved in the glucose response of the rat G-6-Pase gene.

Original languageEnglish (US)
Pages (from-to)E788-E801
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume292
Issue number3
DOIs
StatePublished - Mar 2007

Keywords

  • Adenosine 3′,5′-cyclic monophosphate response element
  • Carbohydrate response element
  • Carbohydrate response element-binding protein
  • Glucose-6-phosphatase
  • Promoter

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