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Targeting the four pillars of enterohepatic bile salt cycling; lessons from genetics and pharmacology

Kunst, R. F., Verkade, H. J., Oude Elferink, R. P. J. & van de Graaf, S. F. J., 22-Nov-2020, In : Hepatology. 22 p.

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  • Targeting the four pillars of enterohepatic bile salt cycling; lessons from genetics and pharmacology

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DOI

Bile salts play a pivotal role in lipid homeostasis, are sensed by specialized receptors and have been implicated in various disorders affecting the gut or liver. They may play a role either as culprit or as potential panacea. Four very efficient transporters mediate the majority of hepatic and intestinal bile salt uptake and efflux, and are each essential for the efficient enterohepatic circulation of bile salts. Starting from the intestinal lumen, conjugated bile salts cross the otherwise impermeable lipid bilayer of (mainly terminal ileal) enterocytes via the Apical Sodium-dependent Bile acid Transporter (ASBT/IBAT; gene SLC10A2) and leave the enterocyte via the basolateral heteromeric Organic Solute Transporter (OST), which consists of an alpha and beta subunit (encoded by SLC51A and SLC51B). The Na+ -Taurocholate Cotransporting polypeptide (NTCP; gene SLC10A1) efficiently clears the portal circulation of bile salts and the apical Bile Salt Export Pump (BSEP; gene ABCB11) pumps the bile salts out of the hepatocyte into primary bile, against a very steep concentration gradient. Recently, individuals lacking either functional NTCP or OST have been described, completing the quartet of bile acid transport deficiencies as ASBT and BSEP deficiencies were already known for years. Novel (patho)physiological insights have been obtained from knockout mice lacking functional expression of these genes and from pharmacological transporter inhibition in mice or humans. CONCLUSION: Here, we provide a concise overview of the 4 main bile salt transport pathways and of their status as possible target of interventions in cholestatic or metabolic disorders.

Original languageEnglish
Number of pages22
JournalHepatology
Publication statusE-pub ahead of print - 22-Nov-2020

ID: 147375820