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

Acta Pharmaceutica Sinica B 2022年第5期12卷 2391-2405页

作者： Peihua Liu Ling Jiang Weimin Kong Qiushi Xie Ping Li Xiaonan Liu Jiayi Zhang Ming Liu Zhongjian Wang Liang Zhu Hanyu Yang Ying Zhou Jianjun Zou Xiaodong Liu Li Liu Center of Drug Metabolism and Pharmacokinetics School of PharmacyChina Pharmaceutical UniversityNanjing 210009China Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy Xuzhou Medical UniversityXuzhou 221004China Department of Clinical Pharmacology Nanjing First HospitalNanjing Medical UniversityNanjing 210006China

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 a)-glucose transporter 2(GLUT2) pathway. The PXR agonists atorvastatin and rifampicin significantly downregulated GLUT2 and HNF4 a expression, and impaired glucose uptake and utilization in HepG2 cells. Overexpression of PXR downregulated GLUT2 and HNF4 a expression, while silencing PXR upregulated HNF4 a and GLUT2 expression.Silencing HNF4 a decreased GLUT2 expression, while overexpressing HNF4 a increased GLUT2 expression and glucose uptake. Silencing PXR or overexpressing HNF4 a reversed the atorvastatininduced decrease in GLUT2 expression and glucose uptake. In human primary hepatocytes, atorvastatin downregulated GLUT2 and HNF4 a mRNA expression, which could be attenuated by silencing PXR. Silencing HNF4 a downregulated GLUT2 mRNA expression. These findings were reproduced with mouse primary hepatocytes. Hnf4 a plasmid increased Slc2 a2 promoter activity. Hnf4 a silencing or pregnenolone-16 a-carbonitrile(PCN) suppressed the Slc2 a2 promoter activity by decreasing HNF4 a recruitment to the Slc2 a2 promoter. Liver-specific Hnf4 a deletion and PCN impaired glucose tolerance and hepatic glucose uptake, and decreased the expression of hepatic HNF4 a and GLUT2. In conclusion, PXR activation impaired hepatic glucose metabolism partly by inhibiting the HNF4 aGLUT2 pathway. These results highlight the molecular mechanisms by which PXR activators induce hyperglycemia/diabetes.

关键词： Pregnane X receptor hepatocyte nuclear factor4-alpha Glucose transporter 2 Hepatic glucose uptake Diabetes Drug-induced hyperglycemia

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