PXR activation impairs hepatic glucose metabolism partly inhibiting the HNF4-GLUT2 pathway.

Drug-induced hyperglycemia/diabetes is a global issue. Some drugs induce hyperglycemia by activating the pregnane X receptor (PXR), but the mechanism is unclear. Here, we report that PXR activation induces hyperglycemia by impairing hepatic glucose metabolism due to inhibition of the hepatocyte nuclear factor 4-alpha (HNF4)‒glucose transporter 2 (GLUT2) pathway. The PXR agonists atorvastatin and rifampicin significantly downregulated GLUT2 and HNF4 expression, and impaired glucose uptake and utilization in HepG2 cells. Overexpression of PXR downregulated GLUT2 and HNF4 expression, while silencing upregulated HNF4 and GLUT2 expression. Silencing decreased GLUT2 expression, while overexpressing HNF4 increased GLUT2 expression and glucose uptake. Silencing or overexpressing HNF4 reversed the atorvastatin-induced decrease in GLUT2 expression and glucose uptake. In human primary hepatocytes, atorvastatin downregulated and mRNA expression, which could be attenuated by silencing . Silencing downregulated mRNA expression. These findings were reproduced with mouse primary hepatocytes. plasmid increased promoter activity. silencing or pregnenolone-16-carbonitrile (PCN) suppressed the promoter activity by decreasing HNF4 recruitment to the promoter. Liver-specific deletion and PCN impaired glucose tolerance and hepatic glucose uptake, and decreased the expression of hepatic HNF4 and GLUT2. In conclusion, PXR activation impaired hepatic glucose metabolism partly by inhibiting the HNF4‒GLUT2 pathway. These results highlight the molecular mechanisms by which PXR activators induce hyperglycemia/diabetes.