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Hochrath, K.* ; Krawczyk, M.* ; Goebel, R.* ; Rathkolb, B. ; Micklich, K. ; Rozman, J. ; Horsch, M. ; Beckers, J. ; Klingenspor, M.* ; Fuchs, H. ; Gailus-Durner, V. ; Wolf, E.* ; Acalovschi, M.* ; Volmer, D. A.* ; Hrabě de Angelis, M. ; Lammert, F.*

The hepatic phosphatidylcholine transporter ABCB4 as modulator of glucose homeostasis.

FASEB J. 26, 5081-5091 (2012)
DOI PMC
The hepatic phosphatidylcholine (PC) transporter ATP-binding cassette (ABC) B4 flops PC from hepatocytes into bile, and its dysfunction causes chronic cholestasis and fibrosis. Because a nuclear receptor-dependent PC pathway has been determined to exert antidiabetic effects, we now analyzed the role of ABCB4 in glucose metabolism. We bred congenic Abcb4-knockout (Abcb4(-/-)) mice on the fibrosis-susceptible BALB/cJ background. Knockout mice and wild-type controls were phenotyped by measuring plasma glucose concentrations, intraperitoneal glucose tolerance, hepatic RNA expression profiles, and liver histology. In addition, 4 procholestatic ABCB4 gene variants were correlated with blood glucose levels in 682 individuals from 2 independent European cohorts. Systemic glucose levels differ significantly between Abcb4(-/-) mice and wild-type controls, and knockout mice display improved glucose tolerance with significantly lower area under the curve values on intraperitoneal glucose challenge. Of note, hepatic expression of the antidiabetic nuclear receptor 5A2 (LRH-1) is induced consistently in Abcb4(-/-) mice, and its specific rare PC ligands are detected in liver by mass spectrometry imaging. In humans, serum glucose levels are associated significantly with the common ABCB4 variant c.711A>T. In summary, ABCB4 might play a critical role in glucose homeostasis in mice and humans. We speculate that the effects could be mediated via LRH-1-dependent PC pathways.-Hochrath, K., Krawczyk, M., Goebel, R., Langhirt, M., Rathkolb, B., Micklich, K., Rozman, J., Horsch, M., Beckers, J., Klingenspor, M., Fuchs, H., Gailus-Durner, V., Wolf, E., Acalovschi, M., Volmer, D. A., Hrabě de Angelis, M., Lammert, F. The hepatic phosphatidylcholine transporter ABCB4 as modulator of glucose homeostasis.
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Publication type Article: Journal article
Document type Scientific Article
Keywords ATP-binding cassette transporter; chronic cholangitis; liver fibrosis; liver receptor homolog; Intrahepatic Cholestasis ; Knockout Mice ; Liver-injury ; Sclerosing Cholangitis ; Insulin-resistance ; Transfer Protein ; Gallstone Risk ; Acid Synthesis ; Bile-acids ; Gene
Language english
Publication Year 2012
HGF-reported in Year 2012
ISSN (print) / ISBN 0892-6638
e-ISSN 1530-6860
Journal FASEB Journal
Quellenangaben Volume: 26, Issue: 12, Pages: 5081-5091 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place Bethesda, Md.
Reviewing status Peer reviewed
Institute(s) Institute of Experimental Genetics (IEG)
POF-Topic(s) 30201 - Metabolic Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-500600-003
G-500600-001
G-500600-004
PubMed ID 22982378
DOI 10.1096/fj.12-209379
WOS ID WOS:000311838300029
Scopus ID 84870330834
Erfassungsdatum 2012-11-05
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