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Non-genetic and epi...
Non-genetic and epigenetic factors contribute to inter-individualvariability of the hepatic bile acid and drug transporter NTCP : Hepatic variability of the hepatic bile acid and drug transporter NTCP
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- Tremmel, Roman (author)
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology
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- van Eijck, Barbara (author)
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology
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- Handin, Niklas (author)
- Uppsala universitet,Institutionen för farmaci
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- Haag, Mathias (author)
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology
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- Winter, Stefan (author)
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology
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- Büttner, Florian (author)
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology
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- Mazzola, Pascale (author)
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology
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- Hofmann, Ute (author)
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology
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- Klein, Kathrin (author)
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology
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- Hoffmann, Per (author)
- University of Bonn,Institute of Human Genetics
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- Nöthen, Markus (author)
- University of Bonn,Institute of Human Genetics
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- Gaugaz, Fabienne Z. (author)
- Uppsala universitet,Institutionen för farmaci,Science for Life Laboratory, SciLifeLab
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- Artursson, Per (author)
- Uppsala universitet,Institutionen för farmaci,Science for Life Laboratory, SciLifeLab
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- Nies, Anne (author)
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology,
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- Schwab, Matthias (author)
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology
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Schaeffeler, Elke (author)
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Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology Institutionen för farmaci (creator_code:org_t)
- English.
- Related links:
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https://urn.kb.se/re...
Abstract
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- Background and Purpose: The hepatic Na+-taurocholate cotransporting polypeptide NTCP/SLC10A1 plays an importantrole in the uptake of bile salts and drugs, and as key receptor for hepatitis B/D virus entry. NTCPinhibitors are investigated for treatment of HBV/HDV-infection. We performed a comprehensivemulti-omics approach to investigate underlying mechanisms of inter-individual variability ofNTCP expression in Caucasians.Experimental Approach: mRNA/protein expression of SLC10A1/NTCP was quantified in 143 well-characterized nontumorhuman liver samples by real-time PCR and LC-MS/MS-based targeted proteomics,respectively. Genetic variants were investigated using genome-wide SNP arrays and nextgenerationsequencing. DNA methylation of the SLC10A1 promoter region was investigatedthrough MALDI-TOF MS. Untargeted metabolomics of liver tissues was performed by UHPLC-QTOFMS.Key Results: The SLC10A1 mRNA expression showed a 44-fold variation in liver samples, whereas NTCPprotein expression varied 10.4-fold. Genome-wide association analyses and in-depth SLC10A1sequencing indicates that genetic variants either in SLC10A1 or other genes, cannot explainexpression variability. Only two missense SLC10A1 variants were identified. NTCP proteinexpression is significantly influenced by non-genetic factors (e.g. smoking, alcoholconsumption). DNA methylation analysis revealed a significant association of specific CpG-siteswith protein expression (p<0.05). Additionally, variable expression is associated with metabolicalterations determined through gene set enrichment and untargeted metabolomics. Findingswere validated partly in livers (n=50) from The Cancer Genome Atlas.Conclusion and Implications: Inter-individual variability of NTCP expression is multifactorial with a significant contribution ofDNA methylation. Functional genetic variants are negligible and may not limit targeting of NTCPby novel inhibitors for treatment of HBV/HDV-infection.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine (hsv//eng)
Keyword
- Na+-taurocholate cotransporting polypeptide (NTCP); SLC10A1; human liver; bile acids; epigenetics
- metabolomics
- HBV/HDV infection
Publication and Content Type
- vet (subject category)
- ovr (subject category)
To the university's database
- By the author/editor
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Tremmel, Roman
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van Eijck, Barba ...
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Handin, Niklas
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Haag, Mathias
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Winter, Stefan
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Büttner, Florian
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show more...
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Mazzola, Pascale
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Hofmann, Ute
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Klein, Kathrin
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Hoffmann, Per
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Nöthen, Markus
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Gaugaz, Fabienne ...
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Artursson, Per
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Nies, Anne
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Schwab, Matthias
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Schaeffeler, Elk ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
- By the university
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Uppsala University