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Review
. 2017;35(3):251-258.
doi: 10.1159/000450983. Epub 2017 Mar 1.

Bile Acid Uptake Transporters as Targets for Therapy

Davor Slijepcevic  1 , Stan F J van de Graaf
Affiliations
Review

Bile Acid Uptake Transporters as Targets for Therapy

Davor Slijepcevic et al. Dig Dis. 2017.

Abstract

Bile acids are potent signaling molecules that regulate glucose, lipid and energy homeostasis predominantly via the bile acid receptors farnesoid X receptor (FXR) and transmembrane G protein-coupled receptor 5 (TGR5). The sodium taurocholate cotransporting polypeptide (NTCP) and the apical sodium dependent bile acid transporter (ASBT) ensure an effective circulation of (conjugated) bile acids. The modulation of these transport proteins affects bile acid localization, dynamics and signaling. The NTCP-specific pharmacological inhibitor myrcludex B inhibits hepatic uptake of conjugated bile acids. Multiple ASBT-inhibitors are already in clinical trials to inhibit intestinal bile acid uptake. Here, we discuss current insights into the consequences of targeting bile acid uptake transporters on systemic and intestinal bile acid dynamics and discuss the possible therapeutic applications that evolve as a result.

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Figures

Fig. 1
Fig. 1
NTCP and ASBT: topology and ligands. Both NTCP (upper panel) and ASBT (lower panel) from the SLC10 family contain 9 transmembrane spanning domains. Conjugated bile acids are natural substrates for these transporters, and recently the preS1 domain of HBV was found to specifically bind to NTCP. Also, the HBV-derived lipopeptide myrcludex B strongly binds to and inhibits NTCP in vitro and in vivo. Many ASBT-specific inhibitors (e.g. A4250) were developed over the past decade to increase fecal bile acid excretion.
Fig. 2
Fig. 2
Enterohepatic circulation of bile acids. a Overview of the distinct hepatic and intestinal bile acid transporters. The key transporters are BSEP, ASBT, OSTα/β, OATP and NTCP (schematically depicted). Upon intracellular bile acid sensing, FXR/SHP and FGF15/19 become activated and regulate bile acid synthesis (i.e. pre-dominantly CYP7A1). Furthermore, spillover of bile acids into the systemic circulation might also activate the TGR5 receptor, present on the basolateral side in various tissues, such as BAT, muscle and in the colon. b Pharmacological inhibition of ileal bile acid uptake (by bile acid binding resins or ASBT inhibitors) induces the presence of bile acids in the colon and increases fecal bile acid loss. The latter contributes to cholesterol catabolism. Increased GLP1 release in the distal intestine improves systemic glucose handling and is likely induced by (passive) the translocation of bile acids leading to basolateral stimulation of TGR5.
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References

    1. Esteller A. Physiology of bile secretion. World J Gastroenterol. 2008;14:5641–5649. - PMC - PubMed
    1. Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem. 2003;72:137–174. - PubMed
    1. Hofmann AF, Sjövall J, Kurz G, et al. A proposed nomenclature for bile acids. J Lipid Res. 1992;33:599–604. - PubMed
    1. Hofmann AF. The enterohepatic circulation of bile acids in mammals: form and functions. Front Biosci (Landmark Ed) 2009;14:2584–2598. - PubMed
    1. Dawson PA, Karpen SJ. Intestinal transport and metabolism of bile acids. J Lipid Res. 2015;56:1085–1099. - PMC - PubMed

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