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A Peroxisome Proliferator-Activated Receptor -Retinoid X Receptor Heterodimer Physically Interacts with the Transcriptional Activator PAX6 to Inhibit Glucagon Gene Transcription

Molecular Pharmacology (R.K., F.F., K.L., M.S., K.R., C.D., E.O., W.K.), Clinical Pharmacology (M.V.T.), and Pediatric Cardiology and Intensive Care Medicine (T.Q.), University of Göttingen, Göttingen, Germany

The peptide hormone glucagon stimulates hepatic glucose output, and its levels in the blood are elevated in type 2 diabetes mellitus. The nuclear receptor peroxisome proliferator-activated receptor- (PPAR) has essential roles in glucose homeostasis, and thiazolidinedione PPAR agonists are clinically important antidiabetic drugs. As part of their antidiabetic effect, thiazolidinediones such as rosiglitazone have been shown to inhibit glucagon gene transcription through binding to PPAR and inhibition of the transcriptional activity of PAX6 that is required for cell-specific activation of the glucagon gene. However, how thiazolidinediones and PPAR inhibit PAX6 activity at the glucagon promoter remained unknown. After transient transfection of a glucagon promoter-reporter fusion gene into a glucagon-producing pancreatic islet -cell line, ligand-bound PPAR was found in the present study to inhibit glucagon gene transcription also after deletion of its DNA-binding domain. Like PPAR ligands, also retinoid X receptor (RXR) agonists inhibited glucagon gene transcription in a PPAR-dependent manner. In glutathione transferase pull-down assays, the ligand-bound PPAR-RXR heterodimer bound to the transactivation domain of PAX6. This interaction depended on the presence of the ligand and RXR, but it was independent of the PPAR DNA-binding domain. Chromatin immunoprecipitation experiments showed that PPAR is recruited to the PAX6-binding proximal glucagon promoter. Taken together, the results of the present study support a model in which a ligand-bound PPAR-RXR heterodimer physically interacts with promoter-bound PAX6 to inhibit glucagon gene transcription. These data define PAX6 as a novel physical target of PPAR-RXR.

Received for publication February 27, 2007.

Accepted for publication October 25, 2007.

Address correspondence to: Dr. Elke Oetjen, Molecular Pharmacology, University of Goettingen, Robert-Koch-Str. 40, 37099 Goettingen, Germany. E-mail: eoetjen{at}med.uni-goettingen.de