Glibenclamide, ATP and metformin increases the expression of human bile salt export pump ABCB11 [version 1; peer review: 1 approved, 2 approved with reservations]
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 intrahepa...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
F1000 Research Ltd
2020-12-01
|
| Series: | F1000Research |
| Online Access: | https://f1000research.com/articles/9-1497/v1 |
| _version_ | 1818879287077371904 |
|---|---|
| author | Nisha Vats Ravi Chandra Dubey Madhusudana Girija Sanal Pankaj Taneja Senthil Kumar Venugopal |
| author_facet | Nisha Vats Ravi Chandra Dubey Madhusudana Girija Sanal Pankaj Taneja Senthil Kumar Venugopal |
| author_sort | Nisha Vats |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T14:27:40Z |
| format | Article |
| id | doaj.art-a67d30726a2e40dd946a2e45133ae7fc |
| institution | Directory Open Access Journal |
| issn | 2046-1402 |
| language | English |
| last_indexed | 2024-12-19T14:27:40Z |
| publishDate | 2020-12-01 |
| publisher | F1000 Research Ltd |
| record_format | Article |
| series | F1000Research |
| spelling | doaj.art-a67d30726a2e40dd946a2e45133ae7fc2022-12-21T20:17:35ZengF1000 Research LtdF1000Research2046-14022020-12-01910.12688/f1000research.26632.129399Glibenclamide, ATP and metformin increases the expression of human bile salt export pump ABCB11 [version 1; peer review: 1 approved, 2 approved with reservations]Nisha Vats0Ravi Chandra Dubey1Madhusudana Girija Sanal2Pankaj Taneja3Senthil Kumar Venugopal4Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, Delhi, 110070, IndiaDepartment of Life Sciences, South Asian University, New Delhi, Delhi, 110021, IndiaDepartment of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, Delhi, 110070, IndiaDepartment of Biotechnology, Sharda University, Noida, Uttar Pradesh, 201310, IndiaDepartment of Life Sciences, South Asian University, New Delhi, Delhi, 110021, IndiaBackground: 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.https://f1000research.com/articles/9-1497/v1 |
| spellingShingle | Nisha Vats Ravi Chandra Dubey Madhusudana Girija Sanal Pankaj Taneja Senthil Kumar Venugopal Glibenclamide, ATP and metformin increases the expression of human bile salt export pump ABCB11 [version 1; peer review: 1 approved, 2 approved with reservations] F1000Research |
| title | Glibenclamide, ATP and metformin increases the expression of human bile salt export pump ABCB11 [version 1; peer review: 1 approved, 2 approved with reservations] |
| title_full | Glibenclamide, ATP and metformin increases the expression of human bile salt export pump ABCB11 [version 1; peer review: 1 approved, 2 approved with reservations] |
| title_fullStr | Glibenclamide, ATP and metformin increases the expression of human bile salt export pump ABCB11 [version 1; peer review: 1 approved, 2 approved with reservations] |
| title_full_unstemmed | Glibenclamide, ATP and metformin increases the expression of human bile salt export pump ABCB11 [version 1; peer review: 1 approved, 2 approved with reservations] |
| title_short | Glibenclamide, ATP and metformin increases the expression of human bile salt export pump ABCB11 [version 1; peer review: 1 approved, 2 approved with reservations] |
| title_sort | glibenclamide atp and metformin increases the expression of human bile salt export pump abcb11 version 1 peer review 1 approved 2 approved with reservations |
| url | https://f1000research.com/articles/9-1497/v1 |
| work_keys_str_mv | AT nishavats glibenclamideatpandmetforminincreasestheexpressionofhumanbilesaltexportpumpabcb11version1peerreview1approved2approvedwithreservations AT ravichandradubey glibenclamideatpandmetforminincreasestheexpressionofhumanbilesaltexportpumpabcb11version1peerreview1approved2approvedwithreservations AT madhusudanagirijasanal glibenclamideatpandmetforminincreasestheexpressionofhumanbilesaltexportpumpabcb11version1peerreview1approved2approvedwithreservations AT pankajtaneja glibenclamideatpandmetforminincreasestheexpressionofhumanbilesaltexportpumpabcb11version1peerreview1approved2approvedwithreservations AT senthilkumarvenugopal glibenclamideatpandmetforminincreasestheexpressionofhumanbilesaltexportpumpabcb11version1peerreview1approved2approvedwithreservations |