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

Progress in the treatment of acquired aplastic anemia in children / 国际儿科学杂志

Aplastic anemia(AA) is a bone marrow failure disease in which peripheral blood is reduced in two or three lines.Clinically, patients are at high risk of bleeding and infection, which may endanger their lives in serious cases.Due to the great differences in economic conditions, medical conditions and AA epidemiology in various regions around the world, there are many treatment methods for newly diagnosed, refractory / relapsed AA patients and their curative effects are different.Haploidentical hematopoietic stem cell transplantation, eltrombopag and tacrolimus are the research focuses in recent years.To facilitate clinicians to choose more appropriate treatments, this paper reviews the progress of hematopoietic stem cell transplantation therapy and non-transplantation therapy in patients with AA.

Progress in diagnosis and treatment of pure red cell aplasia in children / 国际儿科学杂志

Pure red cell aplasia is a rare disease with complex etiology and pathogenesis.It has a variety of treatment methods and therapeutic drugs.This article reviews the etiology,pathogenesis,diagnosis and treatment of pure red cell aplasia in order to help clinicians to have a better understanding of the relevant knowledge of the disease,so as to make timely correct diagnosis and treatment.