Na + -taurocholate cotransporting polypeptide inhibition has hepatoprotective effects in cholestasis in mice
Open accessAbstract
-Taurocholate Cotransporting Polypeptide (NTCP) is the major hepatic uptake transporter of BSs, and can be specifically inhibited by myrcludex B. We hypothesized that inhibition of NTCP dampens cholestatic liver injury. Acute cholestasis was induced in mice by a 3.5-diethoxycarbonyl-1.4-dihydrocollidine (DDC) diet or by bile duct ligation (BDL). Chronic cholestasis was investigated in Atp8b1-G308V and Abcb4/Mdr2 deficient mice. Mice were injected daily with myrcludex B or vehicle. Myrcludex B reduced plasma alkaline phosphatase (ALP) levels in DDC-fed, Atp8b1-G308V and BDL mice by 39%, 27% and 48% respectively. Expression of genes involved in fibrosis, proliferation and inflammation was reduced by myrcludex B treatment in DDC-fed and Atp8b1-G308V mice. NTCP-inhibition increased plasma BS levels from 604±277 to 1746±719 μm in DDC-fed mice, 432±280 to 762±288 μm in Atp8b1-G308V mice and from 522±130 to 3625±378 μm in BDL mice. NTCP-inhibition strongly aggravated weight loss in BDL mice, but not in other cholestatic models studied. NTCP-inhibition reduced biliary BS output in DDC-fed and Atp8b1-G308V mice by ∼50% while phospholipid (PL) output was maintained, resulting in a higher PL/BS ratio. Conversely, liver injury in Abcb4 deficient mice, lacking biliary phospholipid output, was aggravated after myrcludex B treatment. Conclusion: NTCP-inhibition by myrcludex B has hepatoprotective effects, by reducing BS load in hepatocytes and increasing the biliary PL/BS ratio. High micromolar plasma BS levels after NTCP-inhibition were well tolerated. NTCP-inhibition may be beneficial in selected forms of cholestasis. (Hepatology 2018).
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In a chemical mouse model of sclerosing cholangitis, NTCP inhibition by Myrcludex B improved hepatic inflammation and fibrosis.
“In a chemical mouse model of sclerosing cholangitis NTCP inhibition by Myrcludex B improved hepatic inflammation and fibrosis.206”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [206]
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Self-citation
- Authors
- Slijepcevic, D., Roscam Abbing, R. L. P., Fuchs, C. D., Haazen, L. C. M., Beuers, U., Trauner, M., Oude Elferink, R. P. J., & van de Graaf, S. F. J.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology & Hepatology, Amsterdam Gastroenterology and Metabolism,AMC,Amsterdam,the Netherlands
- Medical University of Vienna (AT)
- Venue
- Hepatology
- Published
- 2018-04-27
- Volume
- 68
- Issue
- 3
- Pages
- 1057-1069
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC6175374
- OpenAlex
- W2790870929
- Cited by
- 73
- References
- 37
- Citations by year
- 2026: 8 · 2025: 5 · 2024: 13 · 2023: 4 · 2022: 12 · 2021: 8 · 2020: 8 · 2019: 12 · 2018: 3
- FWCI
- 2.91
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Hepatology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Funders
- Bristol-Myers Squibb
- Gilead Sciences
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (91713319, VIDI 91713319)
- FP7 Ideas: European Research Council (337479)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- normal tissue complication probability, Myrcludex B, bile salt transport, cholestasis, hepatoprotection, bile acid accumulation, ATP8B1, bile duct ligation, liver fibrosis, alkaline phosphatase
- MeSH terms
- Animals, Bile Acids and Salts, Cholestasis, Drug Evaluation, Preclinical, Male, Mice, Inbred C57BL, Phospholipids, Mice, Knockout, Symporters, Organic Anion Transporters, Sodium-Dependent, Lipopeptides
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