Nuclear Receptor PXR; a Novel Glucose Sensor That Regulates Hepatic Gluconeogenesis

Pregnane X receptor (PXR) was originally characterized as a ligand‐activated transcription factor that regulates hepatic drug metabolism and deposition. Here we have determined that PXR as a low glucose response regulator that increases hepatic gluconeogenesis by activating the phosphoenolpyruvate carboxykinase 1 ( Pepck1 ) and glucose 6 phosphatase ( G6Pase ) genes in the livers of fasting mice. Serum/glucocorticoid regulated kinase 2 (SGK2) was found to regulate the PXR‐mediated activation of these genes. Phosphorylated SGK2 at Thr193 repressed the Pepck1 gene by binding to proximal promoter region (‐298/‐180) of the Pepck1 gene in livers of mice under fed condition. In response to fasting, SGK2 was dephosphorylated and dissociated from the promoter to activate the Pepck1 gene only in livers of control mice but not of PXR knockout mice. By utilizing human hepatoma HepG2 cell‐derived ShP51 cells that stably express human PXR, we confirmed that low glucose, but neither insulin nor glucagon, was the cell signal that dephosphorylated SGK2 at Thr193 only when PXR was present. As to the mechanism of Thr193 dephosphorylation, PXR scaffolds protein phosphatase 2C to stimulate it in response to low glucose. Thus, the novel glucose‐PXR‐SGK2 pathway is a novel physiological signaling that increases hepatic gluconeogenesis in response to fasting. Consistent with the lack of this signaling, fasting PXR knockout mice developed hepatic steatosis as observed in PEPCK1 and G6Pase knockout mice (She P et al ., 2000, Mutel E et al ., 2011).