期刊
BIOCHEMICAL PHARMACOLOGY
卷 148, 期 -, 页码 253-264出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2018.01.001
关键词
PXR; GLUT2; GCK; Impaired glucose tolerance; Diabete
资金
- Academy of Finland [286743, 276747]
- Novo Nordisk Foundation [NNF14OC0010653, NNF15OC0015846]
- Duodecim Society of Oulu
- Finnish Medical Foundation
- Finnish Foundation for Cardiovascular Research
- Diabetes Research Foundation
- Novo Nordisk Fonden [NNF14OC0010653, NNF15OC0015846] Funding Source: researchfish
Pregnane X receptor (PXR) is a nuclear receptor that senses chemical environment and is activated by numerous clinically used drugs and environmental contaminants. Previous studies have indicated that several drugs known to activate PXR appear to induce glucose intolerance. We now aimed to reveal the role of PXR in drug-induced glucose intolerance and characterize the mechanisms involved. We used PXR knockout mice model to investigate the significance of this nuclear receptor in the regulation of glucose tolerance. PXR ligand pregnenolone-16a-carbonitrile (PCN) impaired glucose tolerance in the wild type mice but not in the PXR knockout mice. Furthermore, DNA microarray and bioinformatics analysis of differentially expressed genes and glucose metabolism relevant pathways in PCN treated primary hepatocytes indicated that PXR regulates genes involved in glucose uptake. PCN decreased the expression of glucose transporter 2 (GLUT2) in mouse liver and in the wildtype mouse hepatocytes but not in the PXR knockout cells. Data mining of published chromatin immunoprecipitation-sequencing results indicate that Glut2 gene is a direct PXR target. Furthermore, PCN induced internalization of GLUT2 protein from the plasma membrane to the cytosol in the liver in vivo and repressed glucose uptake in the primary hepatocytes. Our results indicate that the activation of PXR impairs glucose tolerance and thus PXR represents a novel diabetogenic pathway. PXR activation dysregulates GLUT2 function by two different mechanisms. These findings may partly explain the diabetogenic effects of medications and environmental contaminants. (C) 2018 Elsevier Inc. All rights reserved.
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