Glibenclamide, ATP and metformin increases the expression of human bile salt export pump ABCB11
Open Access
- 22 December 2020
- journal article
- research article
- Published by F1000 Research Ltd in F1000Research
- Vol. 9, 1497
- https://doi.org/10.12688/f1000research.26632.1
Abstract
Background: Bile salt export pump (BSEP/ABCB11) is important in the maintenance of the enterohepatic circulation of bile acids and drugs. Drugs such as rifampicin and glibenclamide inhibit BSEP. Progressive familial intrahepatic cholestasis type-2, a lethal pediatric disease, some forms of intrahepatic cholestasis of pregnancy, and drug-induced cholestasis are associated with BSEP dysfunction. Methods: We started with a bioinformatic approach to identify the relationship between ABCB11 and other proteins, microRNAs, and drugs. A microarray data set of the liver samples from ABCB11 knockout mice was analyzed using GEO2R. Differentially expressed gene pathway enrichment analysis was conducted using ClueGo. A protein-protein interaction network was constructed using STRING application in Cytoscape. Networks were analyzed using Cytoscape. CyTargetLinker was used to screen the transcription factors, microRNAs and drugs. Predicted drugs were validated on human liver cell line, HepG2. BSEP expression was quantified by real-time PCR and western blotting. Results: ABCB11 knockout in mice was associated with a predominant upregulation and downregulation of genes associated with cellular component movement and sterol metabolism, respectively. We further identified the hub genes in the network. Genes related to immune activity, cell signaling, and fatty acid metabolism were dysregulated. We further identified drugs (glibenclamide and ATP) and a total of 14 microRNAs targeting the gene. Western blot and real-time PCR analysis confirmed the upregulation of BSEP on the treatment of HepG2 cells with glibenclamide, ATP, and metformin. Conclusions: The differential expression of cell signaling genes and those related to immune activity in ABCB11 KO animals may be secondary to cell injury. We have found glibenclamide, ATP, and metformin upregulates BSEP. The mechanisms involved and the clinical relevance of these findings need to be investigated.Keywords
Funding Information
- Science and Engineering Research Board (ECR/2015/000275)
- Department of Biotechnology, Ministry of Science and Technology, India (BT/PR15116/MED/31/334/2016)
This publication has 33 references indexed in Scilit:
- A simple tool to improve pluripotent stem cell differentiationNature Methods, 2013
- NR1H4 analysis in patients with progressive familial intrahepatic cholestasis, drug-induced cholestasis or intrahepatic cholestasis of pregnancy unrelated to ATP8B1, ABCB11 and ABCB4 mutationsClinics and Research in Hepatology and Gastroenterology, 2012
- AMP-activated protein kinase—an energy sensor that regulates all aspects of cell functionGenes & Development, 2011
- Bile Acids Induce Inflammatory Genes in HepatocytesThe American Journal of Pathology, 2011
- Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancyGut, 2008
- Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiencyHepatology, 2006
- Oligonucleotide microarray analysis of differential transporter regulation in the regenerating rat liverLiver International, 2005
- Identification of Transcriptional Networks during Liver RegenerationJournal of Biological Chemistry, 2005
- The ENCODE (ENCyclopedia Of DNA Elements) ProjectScience, 2004
- Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction NetworksGenome Research, 2003