Hepatic uptake of conjugated bile acids is mediated by both sodium taurocholate cotransporting polypeptide and organic anion transporting polypeptides and modulated by intestinal sensing of plasma bile acid levels in mice.

Hepatology : Official Journal of the American Association for the Study of Liver Diseases
Davor SlijepcevicStan F J van de Graaf

Abstract

The Na+ -taurocholate cotransporting polypeptide (NTCP/SLC10A1) is believed to be pivotal for hepatic uptake of conjugated bile acids. However, plasma bile acid levels are normal in a subset of NTCP knockout mice and in mice treated with myrcludex B, a specific NTCP inhibitor. Here, we elucidated which transport proteins mediate the hepatic uptake of conjugated bile acids and demonstrated intestinal sensing of elevated bile acid levels in plasma in mice. Mice or healthy volunteers were treated with myrcludex B. Hepatic bile acid uptake kinetics were determined in wild-type (WT), organic anion transporting polypeptide (OATP) knockout mice (lacking Slco1a/1b isoforms), and human OATP1B1-transgenic mice. Effects of fibroblast growth factor 19 (FGF19) on hepatic transporter mRNA levels were assessed in rat hepatoma cells and in mice by peptide injection or adeno-associated virus-mediated overexpression. NTCP inhibition using myrcludex B had only moderate effects on bile acid kinetics in WT mice, but completely inhibited active transport of conjugated bile acid species in OATP knockout mice. Cholesterol 7α-hydroxylase Cyp7a1 expression was strongly down-regulated upon prolonged inhibition of hepatic uptake of conjugated bile acids. ...Continue Reading

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Citations

Mar 17, 2018·The Journal of Clinical Endocrinology and Metabolism·Cyndya A ShibaoCharles Robb Flynn
Jun 25, 2017·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Paul A Dawson
Jun 12, 2018·Expert Opinion on Drug Metabolism & Toxicology·Petar D PetrovRamiro Jover
Mar 25, 2018·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Davor SlijepcevicStan F J van de Graaf
Apr 1, 2018·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Jorge A BezerraRonald J Sokol
Feb 1, 2019·Parasite Immunology·Najwa NajjarMicheline Piquette-Miller
Aug 21, 2018·Endocrine Reviews·Emmanuel Somm, François R Jornayvaz
Mar 25, 2019·Toxicological Sciences : an Official Journal of the Society of Toxicology·Yutai LiFrank D Sistare
May 12, 2019·British Journal of Pharmacology·Yunjing ZhangWei Jia
May 29, 2019·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Reinout L P Roscam AbbingStan F J van de Graaf
Oct 21, 2019·The Journal of Clinical Endocrinology and Metabolism·Andreas Brønden, Filip K Knop
Mar 3, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Mingqing ChenAlex Sparreboom
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Dec 7, 2017·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·S F J van de Graaf, Davor Slijepcevic
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Feb 23, 2021·Journal of Hepatology·James Lorenzen Boyer, Carol Jean Soroka
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May 2, 2021·Biochimica Et Biophysica Acta. Molecular and Cell Biology of Lipids·Monique D AppelmanStan F J van de Graaf
Nov 23, 2020·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Roni F KunstStan F J van de Graaf
Aug 10, 2021·Liver International : Official Journal of the International Association for the Study of the Liver·Li-Jing DengYuan-Zong Song
Sep 24, 2021·Alimentary Pharmacology & Therapeutics·Benedikt SimbrunnerThomas Reiberger
Jun 30, 2019·Gene Expression·Benjamin L Woolbright, Hartmut Jaeschke

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Methods Mentioned

BETA
FRET

Software Mentioned

GraphPad
GraphPad Prism

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