Aliases: IBAT, ISBT, NTCP2, PBAM
Gene name: Solute carrier family 10 member 2 (SLC10A2)
ASBT is Na-dependent uptake transporter of bile acids and conjugates. It has an important physiological function as the first step in bile acid (BA) reabsorption from the intestine, playing a key role in the enterohepatic recirculation of BAs .
Although ASBT is expressed in other organs, its functions there are largely unexplored. Genetic polymorphisms have been identified, and BA malabsorption is associated with non-functioning ASBT in humans. Diseases of the gastrointestinal tract (GIT) are notoriously difficult to characterize and accurately diagnose, but it appears likely that functionally relevant genetic polymorphisms of ASBT are at least partly implicated in a number of GIT disease states.
Although there are no known drug substrates of ASBT, there are recent reports of potent in vitro inhibition by important drug classes such as calcium channel blockers and statins, which may have previously unrecognized clinical relevance. ASBT has been variously identified as a potential pharmacological target and a mediator for directed drug delivery. While many of these applications still appear to be in the research stages, several ASBT inhibitors have progressed into clinical trials and one of them was recently launched in Japan for the treatment of chronic idiopathic constipation. As there are no clear associations of ASBT with DDI or food-drug interactions, there are no recommendations for ASBT transporter investigation in either the FDA or EMA guidelines.
ASBT is apically expressed in ileal enterocytes, proximal renal tubule cells, large cholangiocytes and gallbladder epithelial cells [2-6]. High mRNA expression has also been reported in the heart, with lower expression in the lung, testes, uterus, placenta, ovaries and brain (GNF SymAtlas, https://biogps.gnf.org).
Function, physiology and clinically significant polymorphisms
ASBT, a Na-dependent uptake transporter consisting of 348 amino acids, is a 43-kDa transmembrane glycoprotein. It has seven predicted transmembrane helices, an extracellular glycosylated amino terminus and a cytosolic carboxyl terminus [7-10]. The cotransport of BAs and Na+ by human ASBT is best explained by a 2:1 Na+: BA coupling stoichiometry, which is consistent with the crystal structure of the bacterial transporter, ASBTNM . ASBT can function as a monomer, dimer and higher order oligomer irrespective of cysteine-mediated covalent bonds, even though cysteine residues are critical for the membrane expression, stability and function of the transporter .
Phosphorylation as a post-translational modulation of ASBT seems to be critical for the functional expression of the transporter. Inhibition of phosphorylation resulted in decreased protein levels, which was attributed to internalization of ASBT from the surface with subsequent degradation via a proteasome-dependent mechanism . Rapid modulation of ASBT function can be achieved by S-acylation, involving the covalent attachment of fatty acids to cysteine residues in the protein. Incubation of HEK293 cells stably transfected with ASBT in the presence of acyltransferase inhibitor significantly reduced ASBT S-acylation, function, and levels on the plasma membrane, suggesting that S-acylation may contribute to targeting ASBT to plasma membrane .
ASBT is most highly expressed in enterocytes, with ASBT-mediated uptake representing the first step in BA reabsorption in the intestine. It is one of a suite of diverse intestinal and hepatic transporters which facilitate the enterohepatic recycling of BAs, and include NTCP, OSTα and β, BSEP and OATPs, amongst others. In the kidney, ASBT may also rescue BAs that have undergone glomerular filtration from urinary excretion , although its precise role in this organ, and in others where it is highly expressed, is largely unexplored.
The physiological substrates for ASBT are the glycine and taurine conjugates of the major BAs cholic acid, deoxycholic acid, chenodeoxycholic acid, and ursodeoxycholic acid [5, 16]. To date, no non-BA-based substrates have been identified for ASBT.
The SLC10A2 gene is localized to 13q33. A large number of SLC10A2 non-synonymous single nucleotide variants have been reported, although most of them are rare and have a tendency to be ethnicity-related. The variants G292A and G431A are associated with impaired taurocholate transport function; however, the clinical influence on altered BA homeostasis is unknown . Association of some polymorphisms with gallstones, primary BA malabsorption, and familial hypertriglyceridemia has been proposed but not confirmed; further obscuring the picture is the fact that loss-of-function variants have been identified in healthy individuals as well .
As there are no known non-BA substrates of ASBT, this transporter is not associated with DDIs. Recently, however, several FDA-approved drugs were shown to function as in vitro ASBT inhibitors, including dihydropyridine calcium channel blockers and HMG-CoA reductase inhibitors . Interestingly, these are reported to be competitive inhibitors. The authors postulate that inhibition of ASBT may result in greater passage of BAs into the colon, and consequently may explain the potential side effects experienced with these drugs, such as diarrhea, gallstone disease, hypertriglyceridemia, or even susceptibility to colon cancer, but they acknowledge that this requires further investigation.
Due to the central role of ASBT in enterohepatic circulation of BAs and conjugates, defects in protein activity or regulation can change the BA signaling via farnesoid X receptor and may contribute to BA-mediated metabolic and cell injury pathways  resulting in the manifestation of a variety of gastrointestinal disorders. For example, a mutation in SLC10A2 which is associated with decreased transporter activity (P290S) was first discovered in a patient diagnosed with Crohn’s disease, a type of inflammatory bowel disease . In addition, mutations in SLC10A2 can cause congenital primary BA malabsorption (PBAM; OMIM:601295), which is a rare idiopathic disorder associated with the interruption of the enterohepatic circulation of BAs, chronic diarrhea, steatorrhea, fat-soluble vitamin malabsorption, and vitamin K deficiency, which may result in intracranial hemorrhage and reduced plasma cholesterol levels [22, 23]. Other disorders associated with intestinal BA malabsorption that likely involve ASBT include familial hypertriglyceridemia [24-26], idiopathic chronic diarrhea , chronic ileitis, cholesterol and black pigment gallstone disease [28, 29], postcholecystectomy diarrhea, irritable bowel syndrome , and susceptibility to colon cancer . In obesity, intestinal BA absorption is increased secondary to increased expression of ASBT .
Inhibition of ASBT by high affinity, non-absorbable inhibitors represents an alternative strategy for the treatment of hypercholesterolemia , and may alleviate liver and bile duct injury in cholestatic disease by reducing BA absorption in the gut . ASBT inhibitors can be divided into two classes: BA derivatives, including BA dimers, and non-BA compounds, including benzothiazepine and benzothiepine analogs, amongst others . In phase I clinical trials, the ASBT inhibitors odevixibat (A4250), volixibat (SHP626) and linerixibat (GSK2330672) decreased serum BA concentrations with increased fecal BA excretion. In phase II trials linerixibat and odevixibat treatment resulted in a rapid and substantial improvement in pruritus, which is a frequent symptom in patients with cholestatic liver disease. The effect of maralixibat (SHP625) and odevixibat on pruritus was also investigated in various cholestatic pediatric liver diseases. Patients reported an improvement in pruritus, which was significantly correlated with reductions in serum BAs . Results of phase III trials in patients with chronic idiopathic constipation showed that elobixibat (A3309) could resolve constipation  and also proved to be useful for treating chronic constipation in hemodialysis patients . Elobixibat was recently launched in Japan for the treatment of chronic idiopathic constipation. A phase III trial investigating the efficacy and safety of odevixibat in pediatric patients with biliary atresia was initiated in 2020 .
Some drugs, especially antibiotics like ampicillin, bacitracin, neomycin, and streptomycin, appear to induce elevated expression of ASBT and thereby enhance intestinal BA absorption .
Due to the specificity and high capacity of the BA transport system, BAs or BA derivative conjugates are attractive leads in prodrug design. Localization on the apical membrane of enterocytes suggests that ASBT may be an effective target for enhancing oral bioavailability, the main goal of transporter-based prodrug design . As an example, conjugation with bile salt oligomers could facilitate oral administration of heparin . In addition, ASBT can serve as a receptor for endocytosis, which can transport macromolecules and nanoparticles, regarded as carriers of various drugs, in the body . In Caco-2 cell monolayers the cellular internalization of deoxycholic acid-modified chitosan nanoparticles loaded with insulin occurred predominantly through the energy-dependent active endocytosis pathway mediated by ASBT . High expression of ASBT in certain tumors also raises the possibility of targeted drug delivery. ASBT could be engaged for selectively targeting a cisplatin-ursodeoxycholate conjugate to cholangiocarcinoma cells .
As there are no associations of ASBT with DDI or food-drug interactions, there are no recommendations for ASBT transporter investigation in either the FDA or EMA guidelines.
1. Hagenbuch, B. and P. Dawson, The sodium bile salt cotransport family SLC10. Pflugers Arch., 2004. 447(5): p. 566-70. Epub 2003 Jul 8.
2. Wong, M.H., et al., Expression cloning and characterization of the hamster ileal sodium-dependent bile acid transporter. J Biol Chem., 1994. 269(2): p. 1340-7.
3. Christie, D.M., et al., Comparative analysis of the ontogeny of a sodium-dependent bile acid transporter in rat kidney and ileum. Am J Physiol., 1996. 271(2 Pt 1): p. G377-85.
4. Lazaridis, K.N., et al., Rat cholangiocytes absorb bile acids at their apical domain via the ileal sodium-dependent bile acid transporter. J Clin Invest., 1997. 100(11): p. 2714-21.
5. Craddock, A.L., et al., Expression and transport properties of the human ileal and renal sodium-dependent bile acid transporter. Am J Physiol., 1998. 274(1 Pt 1): p. G157-69.
6. Chignard, N., et al., Bile acid transport and regulating functions in the human biliary epithelium. Hepatology., 2001. 33(3): p. 496-503.
7. Dawson, P.A. and P. Oelkers, Bile acid transporters. Curr Opin Lipidol., 1995. 6(2): p. 109-14.
8. Hagenbuch, B. and P.J. Meier, Molecular cloning, chromosomal localization, and functional characterization of a human liver Na+/bile acid cotransporter. J Clin Invest., 1994. 93(3): p. 1326-31.
9. Banerjee, A. and P.W. Swaan, Membrane topology of human ASBT (SLC10A2) determined by dual label epitope insertion scanning mutagenesis. New evidence for seven transmembrane domains. Biochemistry., 2006. 45(3): p. 943-53.
10. Zhang, E.Y., et al., Topology scanning and putative three-dimensional structure of the extracellular binding domains of the apical sodium-dependent bile acid transporter (SLC10A2). Biochemistry., 2004. 43(36): p. 11380-92.
11. Hu, N.J., et al., Crystal structure of a bacterial homologue of the bile acid sodium symporter ASBT. Nature, 2011. 478(7369): p. 408-11.
12. Chothe, P.P., et al., Human bile acid transporter ASBT (SLC10A2) forms functional non-covalent homodimers and higher order oligomers. Biochim Biophys Acta Biomembr, 2018. 1860(3): p. 645-653.
13. Chothe, P.P., et al., Tyrosine Phosphorylation Regulates Plasma Membrane Expression and Stability of the Human Bile Acid Transporter ASBT (SLC10A2). Mol Pharm, 2019. 16(8): p. 3569-3576.
14. Ticho, A.L., et al., S-acylation modulates the function of the apical sodium-dependent bile acid transporter in human cells. J Biol Chem, 2020. 295(14): p. 4488-4497.
15. Wilson, F.A., et al., Sodium-coupled taurocholate transport in the proximal convolution of the rat kidney in vivo and in vitro. J Clin Invest., 1981. 67(4): p. 1141-50.
16. Kramer, W., et al., Substrate specificity of the ileal and the hepatic Na(+)/bile acid cotransporters of the rabbit. I. Transport studies with membrane vesicles and cell lines expressing the cloned transporters. J Lipid Res., 1999. 40(9): p. 1604-17.
17. Ho, R.H., et al., Functional characterization of genetic variants in the apical sodium-dependent bile acid transporter (ASBT; SLC10A2). J Gastroenterol Hepatol., 2011. 26(12): p. 1740-8. doi: 10.1111/j.1440-1746.2011.06805.x.
18. Kubitz, R., et al., Genetic variations of bile salt transporters. Drug Discov Today Technol, 2014. 12: p. e55-67.
19. Zheng, X., et al., Computational models for drug inhibition of the human apical sodium-dependent bile acid transporter. Mol Pharm., 2009. 6(5): p. 1591-603.
20. Dawson, P.A., Roles of Ileal ASBT and OSTalpha-OSTbeta in Regulating Bile Acid Signaling. Dig Dis, 2017. 35(3): p. 261-266.
21. Wong, M.H., P. Oelkers, and P.A. Dawson, Identification of a mutation in the ileal sodium-dependent bile acid transporter gene that abolishes transport activity. J Biol Chem., 1995. 270(45): p. 27228-34.
22. Heubi, J.E., et al., Primary bile acid malabsorption: defective in vitro ileal active bile acid transport. Gastroenterology., 1982. 83(4): p. 804-11.
23. Oelkers, P., et al., Primary bile acid malabsorption caused by mutations in the ileal sodium-dependent bile acid transporter gene (SLC10A2). J Clin Invest., 1997. 99(8): p. 1880-7.
24. Angelin, B., K.S. Hershon, and J.D. Brunzell, Bile acid metabolism in hereditary forms of hypertriglyceridemia: evidence for an increased synthesis rate in monogenic familial hypertriglyceridemia. Proc Natl Acad Sci U S A., 1987. 84(15): p. 5434-8.
25. Duane, W.C., et al., Diminished gene expression of ileal apical sodium bile acid transporter explains impaired absorption of bile acid in patients with hypertriglyceridemia. J Lipid Res., 2000. 41(9): p. 1384-9.
26. Love, M.W., et al., Analysis of the ileal bile acid transporter gene, SLC10A2, in subjects with familial hypertriglyceridemia. Arterioscler Thromb Vasc Biol., 2001. 21(12): p. 2039-45.
27. Schiller, L.R., et al., Studies of the prevalence and significance of radiolabeled bile acid malabsorption in a group of patients with idiopathic chronic diarrhea. Gastroenterology., 1987. 92(1): p. 151-60.
28. Holzer, A., et al., Diminished expression of apical sodium-dependent bile acid transporter in gallstone disease is independent of ileal inflammation. Digestion., 2008. 78(1): p. 52-9. Epub 2008 Oct 2.
29. Vitek, L. and M.C. Carey, Enterohepatic cycling of bilirubin as a cause of 'black' pigment gallstones in adult life. Eur J Clin Invest., 2003. 33(9): p. 799-810.
30. Camilleri, M., et al., Measurement of serum 7alpha-hydroxy-4-cholesten-3-one (or 7alphaC4), a surrogate test for bile acid malabsorption in health, ileal disease and irritable bowel syndrome using liquid chromatography-tandem mass spectrometry. Neurogastroenterol Motil., 2009. 21(7): p. 734-e43. Epub 2009 Mar 13.
31. Wang, W., et al., An association between genetic polymorphisms in the ileal sodium-dependent bile acid transporter gene and the risk of colorectal adenomas. Cancer Epidemiol Biomarkers Prev., 2001. 10(9): p. 931-6.
32. Sundaram, S., et al., Mechanism of Dyslipidemia in Obesity-Unique Regulation of Ileal Villus Cell Brush Border Membrane Sodium-Bile Acid Cotransport. Cells, 2019. 8(10).
33. Kramer, W. and H. Glombik, Bile acid reabsorption inhibitors (BARI): novel hypolipidemic drugs. Curr Med Chem., 2006. 13(9): p. 997-1016.
34. Baghdasaryan, A., et al., Inhibition of intestinal bile acid absorption improves cholestatic liver and bile duct injury in a mouse model of sclerosing cholangitis. J Hepatol, 2016. 64(3): p. 674-81.
35. Dawson, P.A., Role of the intestinal bile acid transporters in bile acid and drug disposition. Handb Exp Pharmacol., 2011(201): p. 169-203.
36. Al-Dury, S. and H.U. Marschall, Ileal Bile Acid Transporter Inhibition for the Treatment of Chronic Constipation, Cholestatic Pruritus, and NASH. Front Pharmacol, 2018. 9: p. 931.
37. Nakajima, A., et al., Efficacy, long-term safety, and impact on quality of life of elobixibat in more severe constipation: Post hoc analyses of two phase 3 trials in Japan. Neurogastroenterol Motil, 2019. 31(5): p. e13571.
38. Kamei, D., et al., Elobixibat alleviates chronic constipation in hemodialysis patients: a questionnaire-based study. BMC Gastroenterol, 2020. 20(1): p. 26.
39. Karpen, S.J., et al., Ileal bile acid transporter inhibition as an anticholestatic therapeutic target in biliary atresia and other cholestatic disorders. Hepatol Int, 2020.
40. Miyata, M., et al., Antibacterial drug treatment increases intestinal bile acid absorption via elevated levels of ileal apical sodium-dependent bile acid transporter but not organic solute transporter alpha protein. Biol Pharm Bull, 2015. 38(3): p. 493-6.
41. Al-Hilal, T.A., et al., Oligomeric bile acid-mediated oral delivery of low molecular weight heparin. J Control Release, 2014. 175: p. 17-24.
42. Park, J., et al., Bile acid transporter mediated endocytosis of oral bile acid conjugated nanocomplex. Biomaterials, 2017. 147: p. 145-154.
43. Fan, W., et al., Functional nanoparticles exploit the bile acid pathway to overcome multiple barriers of the intestinal epithelium for oral insulin delivery. Biomaterials, 2018. 151: p. 13-23.
44. Lozano, E., et al., Enhanced antitumour drug delivery to cholangiocarcinoma through the apical sodium-dependent bile acid transporter (ASBT). J Control Release, 2015. 216: p. 93-102.