PXR activation impairs hepatic glucose metabolism partly via inhibiting the HNF4α–GLUT2 pathway

Abstract

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<i>α</i>)‒glucose transporter 2 (GLUT2) pathway. The PXR agonists atorvastatin and rifampicin significantly downregulated GLUT2 and HNF4<i>α</i> expression, and impaired glucose uptake and utilization in HepG2 cells. Overexpression of PXR downregulated GLUT2 and HNF4<i>α</i> expression, while silencing <i>PXR</i> upregulated HNF4<i>α</i> and GLUT2 expression. Silencing <i>HNF4α</i> decreased GLUT2 expression, while overexpressing HNF4<i>α</i> increased GLUT2 expression and glucose uptake. Silencing <i>PXR</i> or overexpressing HNF4<i>α</i> reversed the atorvastatin-induced decrease in GLUT2 expression and glucose uptake. In human primary hepatocytes, atorvastatin downregulated <i>GLUT2</i> and <i>HNF4α</i> mRNA expression, which could be attenuated by silencing <i>PXR</i>. Silencing <i>HNF4α</i> downregulated <i>GLUT2</i> mRNA expression. These findings were reproduced with mouse primary hepatocytes. <i>Hnf4α</i> plasmid increased <i>Slc2a2</i> promoter activity. <i>Hnf4α</i> silencing or pregnenolone-16<i>α</i>-carbonitrile (PCN) suppressed the <i>Slc2a2</i> promoter activity by decreasing HNF4<i>α</i> recruitment to the <i>Slc2a2</i> promoter. Liver-specific <i>Hnf4α</i> deletion and PCN impaired glucose tolerance and hepatic glucose uptake, and decreased the expression of hepatic HNF4<i>α</i> and GLUT2. In conclusion, PXR activation impaired hepatic glucose metabolism partly by inhibiting the HNF4<i>α</i>‒GLUT2 pathway. These results highlight the molecular mechanisms by which PXR activators induce hyperglycemia/diabetes.