Pharmacological inhibition of apical sodium-dependent bile acid transporter changes bile composition and blocks progression of sclerosing cholangitis in multidrug resistance 2 knockout mice
Open accessAbstract
UNLABELLED: Deficiency of multidrug resistance 2 (mdr2), a canalicular phospholipid floppase, leads to excretion of low-phospholipid "toxic" bile causing progressive cholestasis. We hypothesize that pharmacological inhibition of the ileal, apical sodium-dependent bile acid transporter (ASBT), blocks progression of sclerosing cholangitis in mdr2(-/-) mice. Thirty-day-old, female mdr2(-/-) mice were fed high-fat chow containing 0.006% SC-435, a minimally absorbed, potent inhibitor of ASBT, providing, on average, 11 mg/kg/day of compound. Bile acids (BAs) and phospholipids were measured by mass spectrometry. Compared with untreated mdr2(-/-) mice, SC-435 treatment for 14 days increased fecal BA excretion by 8-fold, lowered total BA concentration in liver by 65%, reduced total BA and individual hydrophobic BA concentrations in serum by >98%, and decreased plasma alanine aminotransferase, total bilirubin, and serum alkaline phosphatase levels by 86%, 93%, and 55%, respectively. Liver histology of sclerosing cholangitis improved, and extent of fibrosis decreased concomitant with reduction of hepatic profibrogenic gene expression. Biliary BA concentrations significantly decreased and phospholipids remained low and unchanged with treatment. The phosphatidylcholine (PC)/BA ratio in treated mice corrected toward a ratio of 0.28 found in wild-type mice, indicating decreased bile toxicity. Hepatic RNA sequencing studies revealed up-regulation of putative anti-inflammatory and antifibrogenic genes, including Ppara and Igf1, and down-regulation of several proinflammatory genes, including Ccl2 and Lcn2, implicated in leukocyte recruitment. Flow cytometric analysis revealed significant reduction of frequencies of hepatic CD11b(+) F4/80(+) Kupffer cells and CD11b(+) Gr1(+) neutrophils, accompanied by expansion of anti-inflammatory Ly6C(-) monocytes in treated mdr2(-/-) mice. CONCLUSION: Inhibition of ASBT reduces BA pool size and retention of hydrophobic BA, favorably alters the biliary PC/BA ratio, profoundly changes the hepatic transcriptome, attenuates recruitment of leukocytes, and abrogates progression of murine sclerosing cholangitis.
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The BA sequestrant colesevelam and ASBT inhibitors (lopixibat and A4250) completely reversed liver and bile duct injury in Mdr2/Abcb4-/- mice.
“The BA sequestrant colesevelam and ASBT inhibitors (lopixibat and A4250) completely reversed liver and bile duct injury in Mdr2/Abcb4–/– mice,198–200”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [199]
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Cites
Trapnell, C., Williams, B. A., Pertea, G., Mortazavi, A., Kwan, G., van Baren, M. J., Salzberg, S. L., Wold, B. J., & Pachter, L. (2010) · Nature Biotechnology · doi:10.1038/nbt.1621 · Cited by 15,556 · see citing works
TopHat: discovering splice junctions with RNA-Seq
Trapnell, C., Pachter, L. S., & Salzberg, S. L. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp120 · Cited by 11,477 · see citing works
ToppGene Suite for gene list enrichment analysis and candidate gene prioritization
Chen, J., Bardes, E. E., Aronow, B. J., & Jegga, A. G. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp427 · Cited by 2,952 · see citing works
Self-citationDetergent Properties of Bile Salts: Correlation with Physiological Function
Hofmann, A. F., & SMALL, D. M. (1967) · Annual Review of Medicine · doi:10.1146/annurev.me.18.020167.002001 · Cited by 630 · see citing works
New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond
Beuers, U., Trauner, M., Jansen, P., & Poupon, R. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2015.02.023 · Cited by 537 · see citing works
Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas
Faubion, W. A., Guicciardi, M. E., Miyoshi, H., Bronk, S. F., Roberts, P. J., Svingen, P. A., Kaufmann, S. H., & Gores, G. J. (1999) · Journal of Clinical Investigation · doi:10.1172/jci4765 · Cited by 536 · see citing works
Fickert, P., Fuchsbichler, A., Wagner, M., Zollner, G., Kaser, A., Tilg, H., Krause, R. G. E., Lammert, F., Langner, C., Zatloukal, K., et al. (2004) · Gastroenterology · doi:10.1053/j.gastro.2004.04.009 · Cited by 468 · see citing works
Genome-Wide Association Analysis in Primary Sclerosing Cholangitis
Karlsen, T. H., Franke, A., Melum, E., Kaser, A., Hov, J. R., Balschun, T. C., Lie, B. A., Bergquist, A. M., Schramm, C., Weismüller, T. J., et al. (2009) · Gastroenterology · doi:10.1053/j.gastro.2009.11.046 · Cited by 360 · see citing works
Beuers, U., Hohenester, S., de Buy Wenniger, L. J. M., Kremer, A. E., Jansen, P. L. M., & Elferink, R. P. J. O. (2010) · Hepatology · doi:10.1002/hep.23810 · Cited by 351 · see citing works
Yerushalmi, B. (2001) · Hepatology · doi:10.1053/jhep.2001.22702 · Cited by 343 · see citing works
Ghonem, N. S., Assis, D. N., & Boyer, J. L. (2015) · Hepatology · doi:10.1002/hep.27744 · Cited by 317 · see citing works
Fickert, P., Wagner, M., Marschall, H., Fuchsbichler, A., Zollner, G., Tsybrovskyy, O., Zatloukal, K., Liu, J., Waalkes, M. P., Cover, C., et al. (2006) · Gastroenterology · doi:10.1053/j.gastro.2005.10.018 · Cited by 301 · see citing works
Pathogenesis of cholestatic liver disease and therapeutic approaches
Hirschfield, G. M., Heathcote, E. J., & Gershwin, M. E. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.09.004 · Cited by 287 · see citing works
Apoptosis and hepatobiliary disease
Patel, T. C., & Gores, G. J. (1995) · Hepatology · doi:10.1002/hep.1840210635 · Cited by 275 · see citing works
McMahan, R. H., Wang, X. X., Cheng, L. L., Krisko, T., Smith, M., El Kasmi, K., Pruzanski, M., Adorini, L., Golden-Mason, L., Levi, M., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.446575 · Cited by 225 · see citing works
Wang, D. Q., & Carey, M. C. (1996) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)37603-3 · Cited by 213 · see citing works
Gälman, C., Arvidsson, I., Angelin, B., & Rudling, M. (2003) · Journal of Lipid Research · doi:10.1194/jlr.d200043-jlr200 · Cited by 194 · see citing works
TGR5 potentiates GLP-1 secretion in response to anionic exchange resins
Harach, T., Pols, T. W. H., Nomura, M., Maida, A., 渡辺, 光., Auwerx, J. H., & Schoonjans, K. (2012) · Scientific Reports · doi:10.1038/srep00430 · Cited by 180 · see citing works
Lammert, F., Wang, D. Q. ‐., Hillebrandt, S., Geier, A., Fickert, P., Trauner, M. A., Matern, S., Paigen, B. J., & Carey, M. C. (2004) · Hepatology · doi:10.1002/hep.20022 · Cited by 157 · see citing works
Improved analysis of bile acids in tissues and intestinal contents of rats using LC/ESI-MS
Hagio, M., Matsumoto, M., Fukushima, M., Hara, H., & Ishizuka, S. (2008) · Journal of Lipid Research · doi:10.1194/jlr.d800041-jlr200 · Cited by 153 · see citing works
Effects of bile salts on the plasma membranes of isolated rat hepatocytes
Billington, D. C., Evans, C., Godfrey, P. P., & COLEMAN, R. (1980) · Biochemical Journal · doi:10.1042/bj1880321 · Cited by 144 · see citing works
Cholangiocyte anion exchange and biliary bicarbonate excretion
Bañales, J. M. (2006) · World Journal of Gastroenterology · doi:10.3748/wjg.v12.i22.3496 · Cited by 132 · see citing works
He, H., Mennone, A., Boyer, J. L., & Cai, S.-Y. (2011) · Hepatology · doi:10.1002/hep.24047 · Cited by 119 · see citing works
Ramm, G. A., Shepherd, R. W., Hoskins, A. C., Greco, S. A., Ney, A. D., Pereira, T. N., Bridle, K. R., Doecke, J. D., Meikle, P. J., Turlin, B., et al. (2008) · Hepatology · doi:10.1002/hep.22637 · Cited by 99 · see citing works
Hoegenauer, K., Arista, L., Schmiedeberg, N., Werner, G., Jaksche, H., Bouhelal, R., Nguyen, D. G., Bhat, B. G., Raad, L., Rauld, C., et al. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm501052c · Cited by 96 · see citing works
Lamireau, T., Zoltowska, M., Levy, E. H., Yousef, I. M., Rosenbaum, J., Tuchweber, B., & Desmoulière, A. (2003) · Life Sciences · doi:10.1016/s0024-3205(02)02408-6 · Cited by 91 · see citing works
van Nieuwerk, C. M. J., Groen, A. K., Ottenhoff, R., van Wijland, M., Weerman, M. A. V. D. B., Tytgat, G. N. J., Offerhaus, G. J. A., & Elferink, R. P. J. O. (1997) · Journal of Hepatology · doi:10.1016/s0168-8278(97)80020-7 · Cited by 82 · see citing works
Bile acid secretion, bile flow and biliary lipid secretion in humans.
Hofmann, A. F. (1990) · PubMed · Cited by 80 · see citing works
Liver diseases related to MDR3 (ABCB4) gene deficiency
Gonzales, E. M. (2009) · Frontiers in bioscience · doi:10.2741/3526 · Cited by 79 · see citing works
West, K. L., Zern, T. L., Butteiger, D. N., Keller, B. T., & Fernández, M. L. (2003) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2003.08.019 · Cited by 68 · see citing works
Self-citationLages, C. S., Simmons, J. R., Chougnet, C. A., & Miethke, A. G. (2012) · Hepatology · doi:10.1002/hep.25662 · Cited by 67 · see citing works
Self-citationWest, K. L., Ramjiganesh, T., Roy, S., Keller, B. T., & Fernández, M. L. (2002) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.102.038711 · Cited by 40 · see citing works
Self-citationNew Insights into Autoimmune Cholangitis through Animal Models
Trauner, M. A., Fickert, P., Baghdasaryan, A., Claudel, T., Halilbasic, E., Moustafa, T., Wagner, M., & Zollner, G. (2010) · Digestive Diseases · doi:10.1159/000282072 · Cited by 34 · see citing works
Growth hormone resistance exacerbates cholestasis‐induced murine liver fibrosis
Stiedl, P., McMahon, R., Blaas, L., et al. (2014) · Hepatology · doi:10.1002/hep.27408 · Cited by 29 · see citing works
Proteomic profiling in Lipocalin 2 deficient mice under normal and inflammatory conditions
Labbus, K., Henning, M., Borkham‐Kamphorst, E., Geisler, C., Berger, T., Mak, T. W., Knüchel, R., Meyer, H. E., Weiskirchen, R., & Henkel, C. (2012) · Journal of Proteomics · doi:10.1016/j.jprot.2012.11.021 · Cited by 25 · see citing works
Macri, S. C., Bailey, C. C., de Oca, N. M., Silva, N. A., Rosene, D. L., Mansfield, K. G., & Miller, A. D. (2012) · Toxicologic Pathology · doi:10.1177/0192623311436177 · Cited by 19 · see citing works
Hulzebos, C. V., Voshol, P. J., Wolters, H., et al. (2005) · Liver International · doi:10.1111/j.1478-3231.2005.01036.x · Cited by 8 · see citing works
Golbar, H. M., Izawa, T., Wijesundera, K. K., Tennakoon, A. H., Katou-Ichikawa, C., Tanaka, M., Kuwamura, M., & Yamate, J. (2014) · Journal of Comparative Pathology · doi:10.1016/j.jcpa.2014.05.003 · Cited by 5 · see citing works
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Jansen, P. L. M., Ghallab, A., Vartak, N., Reif, R., Schaap, F. G., Hampe, J., & Hengstler, J. G. (2017) · Hepatology · doi:10.1002/hep.28965 · Cited by 301 · see citing works
New therapeutic concepts in bile acid transport and signaling for management of cholestasis
Trauner, M., Fuchs, C. D., Halilbasic, E., & Paumgartner, G. (2017) · Hepatology · doi:10.1002/hep.28991 · Cited by 227 · see citing works
Intestinal absorption of bile acids in health and disease
Ticho, A. L., Malhotra, P., Dudeja, P. K., Gill, R. K., & Alrefai, W. A. (2019) · Comprehensive physiology · doi:10.1002/cphy.c190007 · Cited by 215 · see citing works
Hegade, V. S., Kendrick, S. F. W., Dobbins, R. L., Miller, S. R., Thompson, D., Richards, D., Storey, J., Dukes, G. E., Corrigan, M., Oude Elferink, R. P. J., et al. (2017) · The Lancet · doi:10.1016/s0140-6736(17)30319-7 · Cited by 206 · see citing works
Rao, A., Kosters, A., Mells, J. E., Zhang, W., Setchell, K. D. R., Amanso, A. M., Wynn, G. M., Xu, T., Keller, B. T., Yin, H., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aaf4823 · Cited by 211 · see citing works
Self-citationNovel therapeutic targets for cholestatic and fatty liver disease
Trauner, M., & Fuchs, C. D. (2022) · Gut · doi:10.1136/gutjnl-2021-324305 · Cited by 204 · see citing works
Baghdasaryan, A., Fuchs, C. D., Österreicher, C. H., Lemberger, U. J., Halilbasic, E., Påhlman, I., Graffner, H., Krones, E., Fickert, P., Wahlström, A., et al. (2016) · Journal of Hepatology · doi:10.1016/j.jhep.2015.10.024 · Cited by 187 · see citing works
ABCB4 gene aberrations in human liver disease: an evolving spectrum
Reichert, M., & Lammert, F. (2018) · Seminars in Liver Disease · doi:10.1055/s-0038-1667299 · Cited by 81 · see citing works
Newsome, P. N., Palmer, M., Freilich, B., Sheikh, M. Y., Sheikh, A., Sarles, H., Herring, R., Mantry, P., Kayali, Z., Hassanein, T., et al. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2020.03.024 · Cited by 80 · see citing works
“SC435 also blocked progression of sclerosing cholangitis and reduced hepatic fibrosis in Mdr2 knockout mice.(32) Phase I studies have demonstrated that volixibat is not metabolized, is minimally absorbed and is effective at reducing serum cholesterol in overweight and obese adults.”
BackgroundFuchs, C. D., Paumgartner, G., Mlitz, V., Kunczer, V., Halilbasic, E., Leditznig, N., Wahlström, A., Ståhlman, M., Thüringer, A., Kashofer, K., et al. (2018) · Gut · doi:10.1136/gutjnl-2017-314553 · Cited by 76 · see citing works
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. (2018) · Hepatology · doi:10.1002/hep.29888 · Cited by 73 · see citing works
- Authors
- Miethke, A. G., Zhang, W., Simmons, J., Taylor, A. E., Shi, T., Shanmukhappa, S. K., Karns, R., White, S., Jegga, A. G., Lages, C. S., Nkinin, S., Keller, B. T., & Setchell, K. D. R.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- Takeda (United States) (US)
- Corresponding author
- Miethke, Alexander G.
- ORCID
- Venue
- Hepatology
- Published
- 2015-08-21
- Volume
- 63
- Issue
- 2
- Pages
- 512-523
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC4713368
- OpenAlex
- W1657692460
- Cited by
- 141
- References
- 38
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 13 · 2023: 8 · 2022: 9 · 2021: 16 · 2020: 20 · 2019: 11 · 2018: 21 · 2017: 17 · 2016: 11 · 2015: 4
- FWCI
- 7.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR001425)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK78392, DK095001, P30DK090971, DK90971, R01DK095001, T32DK007727, P30DK078392)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR47363, P30AR047363)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- ASBT, Mdr2 knockout mice, sclerosing cholangitis, bile acid composition, cholestasis, liver fibrosis, Kupffer cells, neutrophils, monocytes, liver transcriptome, anti-inflammatory genes, bile acid excretion, drug repurposing, cholangiocarcinoma
- MeSH terms
- ATP-Binding Cassette Sub-Family B Member 4, Animals, Bile, Cyclic N-Oxides, Female, Tropanes, Cholangitis, Sclerosing, Mice, Knockout, ATP Binding Cassette Transporter, Subfamily B, Disease Progression, Symporters, Organic Anion Transporters, Sodium-Dependent, Mice
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