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Hepatic Expression of the Na(+)-Taurocholate Cotransporting Polypeptide Is Independent from Genetic Variation

The hepatic Na(+)-taurocholate cotransporting polypeptide NTCP/SLC10A1 is important for the uptake of bile salts and selected drugs. Its inhibition results in increased systemic bile salt concentrations. NTCP is also the entry receptor for the hepatitis B/D virus. We investigated interindividual hep...

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Autores principales: Tremmel, Roman, Nies, Anne T., van Eijck, Barbara A. C., Handin, Niklas, Haag, Mathias, Winter, Stefan, Büttner, Florian A., Kölz, Charlotte, Klein, Franziska, Mazzola, Pascale, Hofmann, Ute, Klein, Kathrin, Hoffmann, Per, Nöthen, Markus M., Gaugaz, Fabienne Z., Artursson, Per, Schwab, Matthias, Schaeffeler, Elke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9267852/
https://www.ncbi.nlm.nih.gov/pubmed/35806468
http://dx.doi.org/10.3390/ijms23137468
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author Tremmel, Roman
Nies, Anne T.
van Eijck, Barbara A. C.
Handin, Niklas
Haag, Mathias
Winter, Stefan
Büttner, Florian A.
Kölz, Charlotte
Klein, Franziska
Mazzola, Pascale
Hofmann, Ute
Klein, Kathrin
Hoffmann, Per
Nöthen, Markus M.
Gaugaz, Fabienne Z.
Artursson, Per
Schwab, Matthias
Schaeffeler, Elke
author_facet Tremmel, Roman
Nies, Anne T.
van Eijck, Barbara A. C.
Handin, Niklas
Haag, Mathias
Winter, Stefan
Büttner, Florian A.
Kölz, Charlotte
Klein, Franziska
Mazzola, Pascale
Hofmann, Ute
Klein, Kathrin
Hoffmann, Per
Nöthen, Markus M.
Gaugaz, Fabienne Z.
Artursson, Per
Schwab, Matthias
Schaeffeler, Elke
author_sort Tremmel, Roman
collection PubMed
description The hepatic Na(+)-taurocholate cotransporting polypeptide NTCP/SLC10A1 is important for the uptake of bile salts and selected drugs. Its inhibition results in increased systemic bile salt concentrations. NTCP is also the entry receptor for the hepatitis B/D virus. We investigated interindividual hepatic SLC10A1/NTCP expression using various omics technologies. SLC10A1/NTCP mRNA expression/protein abundance was quantified in well-characterized 143 human livers by real-time PCR and LC-MS/MS-based targeted proteomics. Genome-wide SNP arrays and SLC10A1 next-generation sequencing were used for genomic analyses. SLC10A1 DNA methylation was assessed through MALDI-TOF MS. Transcriptomics and untargeted metabolomics (UHPLC-Q-TOF-MS) were correlated to identify NTCP-related metabolic pathways. SLC10A1 mRNA and NTCP protein levels varied 44-fold and 10.4-fold, respectively. Non-genetic factors (e.g., smoking, alcohol consumption) influenced significantly NTCP expression. Genetic variants in SLC10A1 or other genes do not explain expression variability which was validated in livers (n = 50) from The Cancer Genome Atlas. The identified two missense SLC10A1 variants did not impair transport function in transfectants. Specific CpG sites in SLC10A1 as well as single metabolic alterations and pathways (e.g., peroxisomal and bile acid synthesis) were significantly associated with expression. Inter-individual variability of NTCP expression is multifactorial with the contribution of clinical factors, DNA methylation, transcriptional regulation as well as hepatic metabolism, but not genetic variation.
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spelling pubmed-92678522022-07-09 Hepatic Expression of the Na(+)-Taurocholate Cotransporting Polypeptide Is Independent from Genetic Variation Tremmel, Roman Nies, Anne T. van Eijck, Barbara A. C. Handin, Niklas Haag, Mathias Winter, Stefan Büttner, Florian A. Kölz, Charlotte Klein, Franziska Mazzola, Pascale Hofmann, Ute Klein, Kathrin Hoffmann, Per Nöthen, Markus M. Gaugaz, Fabienne Z. Artursson, Per Schwab, Matthias Schaeffeler, Elke Int J Mol Sci Article The hepatic Na(+)-taurocholate cotransporting polypeptide NTCP/SLC10A1 is important for the uptake of bile salts and selected drugs. Its inhibition results in increased systemic bile salt concentrations. NTCP is also the entry receptor for the hepatitis B/D virus. We investigated interindividual hepatic SLC10A1/NTCP expression using various omics technologies. SLC10A1/NTCP mRNA expression/protein abundance was quantified in well-characterized 143 human livers by real-time PCR and LC-MS/MS-based targeted proteomics. Genome-wide SNP arrays and SLC10A1 next-generation sequencing were used for genomic analyses. SLC10A1 DNA methylation was assessed through MALDI-TOF MS. Transcriptomics and untargeted metabolomics (UHPLC-Q-TOF-MS) were correlated to identify NTCP-related metabolic pathways. SLC10A1 mRNA and NTCP protein levels varied 44-fold and 10.4-fold, respectively. Non-genetic factors (e.g., smoking, alcohol consumption) influenced significantly NTCP expression. Genetic variants in SLC10A1 or other genes do not explain expression variability which was validated in livers (n = 50) from The Cancer Genome Atlas. The identified two missense SLC10A1 variants did not impair transport function in transfectants. Specific CpG sites in SLC10A1 as well as single metabolic alterations and pathways (e.g., peroxisomal and bile acid synthesis) were significantly associated with expression. Inter-individual variability of NTCP expression is multifactorial with the contribution of clinical factors, DNA methylation, transcriptional regulation as well as hepatic metabolism, but not genetic variation. MDPI 2022-07-05 /pmc/articles/PMC9267852/ /pubmed/35806468 http://dx.doi.org/10.3390/ijms23137468 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tremmel, Roman
Nies, Anne T.
van Eijck, Barbara A. C.
Handin, Niklas
Haag, Mathias
Winter, Stefan
Büttner, Florian A.
Kölz, Charlotte
Klein, Franziska
Mazzola, Pascale
Hofmann, Ute
Klein, Kathrin
Hoffmann, Per
Nöthen, Markus M.
Gaugaz, Fabienne Z.
Artursson, Per
Schwab, Matthias
Schaeffeler, Elke
Hepatic Expression of the Na(+)-Taurocholate Cotransporting Polypeptide Is Independent from Genetic Variation
title Hepatic Expression of the Na(+)-Taurocholate Cotransporting Polypeptide Is Independent from Genetic Variation
title_full Hepatic Expression of the Na(+)-Taurocholate Cotransporting Polypeptide Is Independent from Genetic Variation
title_fullStr Hepatic Expression of the Na(+)-Taurocholate Cotransporting Polypeptide Is Independent from Genetic Variation
title_full_unstemmed Hepatic Expression of the Na(+)-Taurocholate Cotransporting Polypeptide Is Independent from Genetic Variation
title_short Hepatic Expression of the Na(+)-Taurocholate Cotransporting Polypeptide Is Independent from Genetic Variation
title_sort hepatic expression of the na(+)-taurocholate cotransporting polypeptide is independent from genetic variation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9267852/
https://www.ncbi.nlm.nih.gov/pubmed/35806468
http://dx.doi.org/10.3390/ijms23137468
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