Human Transporters

ASBT

ASBT (apical sodium-dependent bile acid transporter)


Aliases: IBAT, ISBT, NTCP2, PBAM
Gene name: Solute carrier family 10 member 2 (SLC10A2)

Summary

ASBT is Na-dependent uptake transporter of bile acids and conjugates. It has an important physiological function as the first step in bile acid reabsorption from the intestine, playing a key role in the enterohepatic recirculation of bile acids [1]. Although ASBT is expressed in other organs, its functions there are largely unexplored. Genetic polymorphisms have been identified, and bile acid 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.
Whilst 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. However, these applications still appear to be in the research stages. 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.

Localization

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, http://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 an extracellular glycosylated amino terminus and a cytosolic carboxyl terminus. It has seven predicted transmembrane helices [7-10], and can function as a monomer or a homomultimer.
ASBT is most highly expressed in enterocytes, with ASBT-mediated uptake representing the first step in bile acid reabsorption in the intestine. It is one of a suite of diverse intestinal and hepatic transporters which facilitate the enterohepatic recycling of bile acids, and include NTCP, OSTα and β, BSEP and OATPs, amongst others. In the kidney, ASBT may also rescue bile acids that have undergone glomerular filtration from urinary excretion [11], 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 bile acids, cholic acid, deoxycholic acid, chenodeoxycholic acid, and ursodeoxycholic acid [5, 12]. To date, no non-bile acid-based substrates have been identified for ASBT.
A large number of non-synonymous single nucleotide variants have been reported in the SLC10A2 gene, 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 bile acid homeostasis is unknown [13]. Association of some polymorphisms with gallstones, primary bile acid 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 [14].

Clinical significance

As there are no known non-bile acid 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 [15]. Interestingly, these are reported to be competitive inhibitors. The authors postulate that inhibition of ASBT may result in greater passage of bile acids 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 bile acids and conjugates, defects in protein activity or regulation may manifest in 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 [16]. In addition, mutations in SLC10A2 can cause congenital primary bile acid malabsorption (PBAM; OMIM:601295), which is a rare idiopathic disorder associated with the interruption of the enterohepatic circulation of bile acids, chronic diarrhea, steatorrhea, fat-soluble vitamin malabsorption, and vitamin K deficiency, which may result in intracranial hemorrhage and reduced plasma cholesterol levels [17, 18]. Other disorders associated with intestinal bile acid malabsorption that likely involve ASBT include familial hypertriglyceridemia [19-21], idiopathic chronic diarrhea [22], chronic ileitis, cholesterol and black pigment gallstone disease [23, 24], postcholecystectomy diarrhea, irritable bowel syndrome [25], and susceptibility to colon cancer [26].
Inhibition of ASBT by high affinity, non-absorbable inhibitors represents an alternative strategy for the treatment of hypercholesterolemia [27], and may alleviate liver and bile duct injury in cholestatic disease by reducing bile salt absorption in the gut [28]. ASBT inhibitors can be divided into two classes: bile acid derivatives, including bile acid dimers, and non-bile acid compounds, including benzothiazepine and benzothiepine analogs [29]. Other drugs, especially antibiotics like ampicillin, bacitracin, neomycin, and streptomycin, appear to induce elevated expression of ASBT and thereby enhance intestinal bile acid absorption [30].
Due to the specificity and high capacity of the bile acid transport system, intensive efforts have been directed at using bile acids or bile acid derivative conjugates 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 [29]. As an example, conjugation with bile salt oligomers could facilitate oral administration of heparin [31]. 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 [32].

Regulatory requirements

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.

Location
Endogenous substrates
Substrates used experimentally
Substrate drugs
Inhibitors
intestine, kidney, cholangiocytes,  gallbladder
Conjugated and unconjugated bile acids, Taurocholic acid
Bile acids such as taurochenodeoxycholate, taurodeoxycholate, glycocholate taurocholate
Dimeric bile acid analogues Benzothiazepine and Benzothiepene derivates and naphtol derivates
Dihydropyridine calcium channel blockers statins, HMG CoA reductase inhibitors (statins)

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.    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.
12.    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.
13.    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.
14.    Kubitz, R., et al., Genetic variations of bile salt transporters. Drug Discov Today Technol, 2014. 12: p. e55-67.
15.    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.
16.    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.
17.    Heubi, J.E., et al., Primary bile acid malabsorption: defective in vitro ileal active bile acid transport. Gastroenterology., 1982. 83(4): p. 804-11.
18.    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.
19.    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.
20.    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.
21.    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.
22.    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.
23.    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.
24.    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.
25.    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.
26.    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.
27.    Kramer, W. and H. Glombik, Bile acid reabsorption inhibitors (BARI): novel hypolipidemic drugs. Curr Med Chem., 2006. 13(9): p. 997-1016.
28.    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.
29.    Dawson, P.A., Role of the intestinal bile acid transporters in bile acid and drug disposition. Handb Exp Pharmacol., 2011(201): p. 169-203.
30.    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.
31.    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.
32.    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.

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