PXR activation impairs hepatic glucose metabolism partly via inhibiting the HNF4a-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 alpha)-glucose transporter 2 (GLUT2) pathway. The PXR agonists atorvastatin and rifampicin significantly downregulated GLUT2 and HNF4 alpha expression, and impaired glucose uptake and utilization in HepG2 cells. Overexpression of PXR downregulated GLUT2 and HNF4 alpha expression, while silencing PXR upregulated HNF4 alpha and GLUT2 expression. Silencing HNF4 alpha decreased GLUT2 expression, while overexpressing HNF4 alpha increased GLUT2 expression and glucose uptake. Silencing PXR or overexpressing HNF4 alpha reversed the atorvastatininduced decrease in GLUT2 expression and glucose uptake. In human primary hepatocytes, atorvastatin downregulated GLUT2 and HNF4 alpha mRNA expression, which could be attenuated by silencing PXR. Silencing HNF4 alpha downregulated GLUT2 mRNA expression. These findings were reproduced with mouse primary hepatocytes. HNF4 alpha plasmid increased Slc2a2 promoter activity. HNF4 alpha silencing or pregnenolone-16a-carbonitrile (PCN) suppressed the Slc2a2 promoter activity by decreasing HNF4 alpha recruitment to the Slc2a2 promoter. Liver-specific HNF4 alpha deletion and PCN impaired glucose tolerance and hepatic glucose uptake, and decreased the expression of hepatic HNF4 alpha and GLUT2. In conclusion, PXR activation impaired hepatic glucose metabolism partly by inhibiting the HNF4 alpha. GLUT2 pathway. These results highlight the molecular mechanisms by which PXR activators induce hyperglycemia/diabetes. (C) 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.

Automated summary

This study found that the activation of pregnane X receptor (PXR) impairs hepatic glucose metabolism by inhibiting the hepatocyte nuclear factor 4-alpha (HNF4 alpha)-glucose transporter 2 (GLUT2) pathway, leading to hyperglycemia. These findings highlight the molecular mechanisms by which PXR activators induce hyperglycemia/diabetes.