- •ASBT deficiency in mice markedly reduced bile duct ligation-induced liver injury.
- •Systemic ASBT inactivation lowered total bile salt pool size.
- •Systemic ASBT inactivation increased renal bile salt excretion.
- •Reduced bile salt pool size before cholestasis onset improved liver injury.
Background & Aims
Abbreviations:ALT (alanine transaminase), ASBT (apical sodium-dependent bile acid transporter), ASBTi (ASBT inhibitors), AST (aspartate transaminase), BDL (bile duct ligation), CCl4 (carbon tetrachloride), CK7 (cytokeratin 7), FRET (Förster resonance energy transfer), G-OCA (glycine-conjugated OCA), HepG2 cell (hepatocarcinoma cell), MDR2 (multidrug resistance protein 2), NASH (non-alcoholic steatohepatitis), NGM282 (non-tumorigenic fibroblast growth factor 19 analogue), NTCP (Na+/taurocholate cotransporting polypeptide), NucleoBAS (nuclear Bile Acid Sensor), OCA (obeticholic acid), PBC (primary biliary cholangitis), PentaOH (pentahydroxylated), RT-qPCR (real-time quantitative PCR), TCA (taurocholic acid), TetraOH (tetrahydroxylated), T-OCA (taurine-conjugated OCA), U2OS (osteosarcoma cell), UHPLC-MS (ultrahigh-performance liquid chromatography mass spectrometry), WT (wild-type)
Materials and methods
Animals and experimental design
Cell culture and treatment
Cell viability assay
Confocal microscopy-based FRET bile acid sensor
3H-TCA uptake assay
RNA isolation and RT-qPCR
Bile salt analysis
Histology and immunohistochemistry
Deficiency of ASBT has hepatoprotective effects after BDL in mice
ASBT deficiency reduces total bile salt pool size and increases urinary bile salt excretion
Reduced pool size before onset of cholestasis alleviates cholestasis-induced liver injury in mice
OCA conjugates are substrates for the bile salt transporters ASBT and NTCP
Hepatoprotective effects as a result of OCA + ASBTi treatment are a direct consequence of reduced toxic bile acid accumulation
- Fuchs C.D.
- Dixon E.D.
- Hendrikx T.
- Mlitz V.
- Wahlström A.
- Ståhlman M.
- et al.
Data availability statement
Conflicts of interest
- Multimedia component 1
- Multimedia component 2
- Multimedia component 3
- Inhibition of intestinal bile acid absorption improves cholestatic liver and bile duct injury in a mouse model of sclerosing cholangitis.J Hepatol. 2016; 64: 674-681
- The ileal bile acid transporter inhibitor A4250 decreases serum bile acids by interrupting the enterohepatic circulation.Aliment Pharmacol Ther. 2016; 43: 303-310
- Effect of ileal bile acid transporter inhibitor GSK2330672 on pruritus in primary biliary cholangitis: a double-blind, randomised, placebo-controlled, crossover, phase 2a study.Lancet. 2017; 389: 1114-1123
- A randomized, controlled, phase 2 study of maralixibat in the treatment of itching associated with primary biliary cholangitis.Hepatol Commun. 2019; 3: 365-381
- BAT117213: ileal bile acid transporter (IBAT) inhibition as a treatment for pruritus in primary biliary cirrhosis: study protocol for a randomised controlled trial.BMC Gastroenterol. 2016; 16: 71
- Ileal bile acid transporter inhibition for the treatment of chronic constipation, cholestatic pruritus, and NASH.Front Pharmacol. 2018; 9: 931
- Volixibat in adults with non-alcoholic steatohepatitis: 24-week interim analysis from a randomized, phase II study.J Hepatol. 2020; 73: 231-240
- Targeted deletion of the ileal bile acid transporter eliminates enterohepatic cycling of bile acids in mice.J Biol Chem. 2003; 278: 33920-33927
- Discovery of a highly potent, nonabsorbable apical sodium-dependent bile acid transporter inhibitor (GSK2330672) for treatment of type 2 diabetes.J Med Chem. 2013; 56: 5094-5114
- Monitoring bile acid transport in single living cells using a genetically encoded Förster resonance energy transfer sensor.Hepatology. 2013; 57: 740-752
- Real time monitoring of intracellular bile acid dynamics using a genetically encoded FRET-based bile acid sensor.J Vis Exp. 2016; 53659
- Homo- and hetero-dimeric architecture of the human liver Na⁺-dependent taurocholate co-transporting protein.Biochem J. 2012; 441: 1007-1015
- Two new human cholangiocarcinoma cell lines and their cytogenetics and responses to growth factors, hormones, cytokines or immunologic effector cells.Int J Cancer. 1992; 52: 252-260
- Assumption-free analysis of quantitative real-time polymerase chain reaction (PCR) data.Neurosci Lett. 2003; 339: 62-66
- Impaired uptake of conjugated bile acids and hepatitis b virus pres1-binding in na+-taurocholate cotransporting polypeptide knockout mice.Hepatology. 2015; 62: 207-219
- Metabolomics and lipidomics in Caenorhabditis elegans using a single-sample preparation.Dis Model Mech. 2021; 14dmm047746
- Nod2 deficiency protects mice from cholestatic liver disease by increasing renal excretion of bile acids.J Hepatol. 2014; 60: 1259-1267
- Mouse organic solute transporter alpha deficiency enhances renal excretion of bile acids and attenuates cholestasis.Hepatology. 2010; 51: 181-190
- Regulation of renal tubular bile acid transport in the early phase of an obstructive cholestasis in the rat.Nephron Physiol. 2003; 95: p49-p56
- Adaptive regulation of bile salt transporters in kidney and liver in obstructive cholestasis in the rat.Gastroenterology. 2001; 121: 1473-1484
- Engineered fibroblast growth factor 19 reduces liver injury and resolves sclerosing cholangitis in Mdr2-deficient mice.Hepatology. 2016; 63: 914-929
- The case for combining treatments for primary sclerosing cholangitis.Lancet Gastroenterol Hepatol. 2018; 3: 526-528
- A new mechanism of obeticholic acid on NASH treatment by inhibiting NLRP3 inflammasome activation in macrophage.Metabolism. 2021; 120154797
- Tetrahydroxylated bile acids improve cholestatic liver and bile duct injury in the Mdr2(-/-) mouse model of sclerosing cholangitis via immunomodulatory effects.Hepatol Commun. 2022; https://doi.org/10.1002/hep4.1998
- The protective role of hydrophilic tetrahydroxylated bile acids (THBA).Biochim Biophys Acta Mol Cell Biol Lipids. 2021; 1866: 158925
Author names in bold designate shared co-first authorship
User LicenseCreative Commons Attribution (CC BY 4.0) |
- Read, print & download
- Redistribute or republish the final article
- Text & data mine
- Translate the article
- Reuse portions or extracts from the article in other works
- Sell or re-use for commercial purposes
Elsevier's open access license policy