Genetic Variations of the ABC Transporter Gene ABCB11 Encoding the Human Bile Salt Export Pump (BSEP) in a Japanese Population

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.

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P0358 FUNCTIONAL ANALYSIS OF THE TRANSCRIPTIONAL REGULATION OF THE HUMAN BILE SALT EXPORT PUMP GENE

Journal of Pediatric Gastroenterology and Nutrition ◽

10.1097/00005176-200406001-00482 ◽

2004 ◽

Vol 39 (Supplement 1) ◽

pp. S192-S193

Author(s):

J. A. Byrne ◽

S. S. Strautnieks ◽

G. Mieli-Vergani ◽

R. J. Thompson

Keyword(s):

Functional Analysis ◽

Transcriptional Regulation ◽

Bile Salt ◽

Bile Salt Export Pump ◽

Human Bile

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Genetic Variation and Haplotype Structure of the ABC Transporter Gene ABCG2 in a Japanese Population

Drug Metabolism and Pharmacokinetics ◽

10.2133/dmpk.21.109 ◽

2006 ◽

Vol 21 (2) ◽

pp. 109-121 ◽

Cited By ~ 30

Author(s):

Keiko Maekawa ◽

Masaya Itoda ◽

Kimie Sai ◽

Yoshiro Saito ◽

Nahoko Kaniwa ◽

...

Keyword(s):

Genetic Variation ◽

Abc Transporter ◽

Japanese Population ◽

Haplotype Structure ◽

Transporter Gene

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The mechanism of increased biliary lipid secretion in mice with genetic inactivation of bile salt export pump

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00391.2014 ◽

2015 ◽

Vol 308 (5) ◽

pp. G450-G457 ◽

Cited By ~ 1

Author(s):

K. E. R. Gooijert ◽

R. Havinga ◽

H. Wolters ◽

R. Wang ◽

V. Ling ◽

...

Keyword(s):

Protein Expression ◽

Bile Salt ◽

Biliary Secretion ◽

Biliary Lipid ◽

Bile Salt Export Pump ◽

Human Bile ◽

Lipid Secretion ◽

Canalicular Transporters ◽

Expression Potential ◽

And Control

Human bile salt export pump ( BSEP) mutations underlie progressive familial intrahepatic cholestasis type 2 (PFIC2). In the PFIC2 animal model, Bsep−/−mice, biliary secretion of bile salts (BS) is decreased, but that of phospholipids (PL) and cholesterol (CH) is increased. Under physiological conditions, the biliary secretion of PL and CH is positively related (“coupled”) to that of BS. We aimed to elucidate the mechanism of increased biliary lipid secretion in Bsep−/−mice. The secretion of the BS tauro-β-muricholic acid (TβMCA) is relatively preserved in Bsep−/−mice. We infused Bsep−/−and Bsep+/+(control) mice with TβMCA in stepwise increasing dosages (150–600 nmol/min) and determined biliary bile flow, BS, PL, and CH secretion. mRNA and protein expression of relevant canalicular transporters was analyzed in livers from noninfused Bsep−/−and control mice. TβMCA infusion increased BS secretion in both Bsep−/−and control mice. The secreted PL or CH amount per BS, i.e., the “coupling,” was continuously two- to threefold higher in Bsep−/−mice ( P < 0.05). Hepatic mRNA expression of canalicular lipid transporters Mdr2, Abcg5, and Abcg8 was 45–55% higher in Bsep−/−mice (Abcg5; P < 0.05), as was canalicular Mdr2 and Abcg5 protein expression. Potential other explanations for the increased coupling of the biliary secretion of PL and CH to that of BS in Bsep−/−mice could be excluded. We conclude that the mechanism of increased biliary lipid secretion in Bsep−/−mice is based on increased expression of the responsible canalicular transporter proteins.

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