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Area of Science:

  • Metabolic regulation
  • Nuclear receptor signaling
  • Nutritional genomics

Background:

  • The pregnane X receptor (PXR) is a key regulator of glucose and lipid metabolism.
  • Limited understanding exists regarding how nutritional status influences PXR activity and its downstream gene regulation.

Purpose of the Study:

  • To investigate the genome-wide effects of nutritional status on PXR-mediated gene regulation in the liver.
  • To elucidate the crosstalk between PXR and energy homeostasis under varying nutritional conditions.

Main Methods:

  • Mice were treated with a PXR ligand (PCN) and subjected to fasting or glucose feeding.
  • Gene expression profiling using microarrays was performed.
  • PXR knockout mice were used to validate findings.
  • Primary hepatocytes were used to assess the impact of glucose, insulin, and glucagon.

Main Results:

  • Nutritional status, particularly glucose feeding, significantly modulated the PXR-regulated transcriptome, inducing or repressing a higher number of genes.
  • Glucose potentiated the induction of established PXR target genes.
  • A subset of genes, including Cyp8b1 involved in bile acid synthesis, showed opposing responses to fasting and glucose feeding.
  • PXR knockout abolished these nutritional effects, and PCN altered bile acid composition in glucose-fed mice.

Conclusions:

  • Nutritional status profoundly impacts PXR-regulated gene expression both qualitatively and quantitatively.
  • A complex crosstalk exists between PXR and the regulation of energy homeostasis.
  • These findings highlight the intricate relationship between nutrient availability and nuclear receptor-mediated metabolic control.