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Targeting the Four Pillars of Enterohepatic Bile Salt Cycling; Lessons From Genetics and Pharmacology

Journal

HEPATOLOGY
Volume 73, Issue 6, Pages 2577-2585

Publisher

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1002/hep.31651

Keywords

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Funding

  1. European Society of Pediatric Gastroenterology, Hepatology and Nutrition
  2. University Medical Center of Groningen
  3. C&W de Boer Stichting
  4. Dutch Cancer Foundation [11652]
  5. Dioraphte Foundation
  6. Amsterdam University Medical Centers
  7. Albireo
  8. Mirum

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Bile salts are essential for lipid homeostasis and can be both culprits and potential remedies in gut or liver disorders. Efficient transporters mediate the uptake and efflux of bile salts, ensuring their enterohepatic circulation. Deficiencies in key transporters can lead to pathological conditions, and targeting these pathways may offer new therapeutic opportunities.
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 most of the 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 (primarily terminal ileal) enterocytes through the apical sodium-dependent bile acid transporter (gene SLC10A2) and leave the enterocyte through the basolateral heteromeric organic solute transporter, which consists of an alpha and beta subunit (encoded by SLC51A and SLC51B). The Na+-taurocholate cotransporting polypeptide (gene SLC10A1) efficiently clears the portal circulation of bile salts, and the apical bile salt export pump (gene ABCB11) pumps the bile salts out of the hepatocyte into primary bile, against a very steep concentration gradient. Recently, individuals lacking either functional Na+-taurocholate cotransporting polypeptide or organic solute transporter have been described, completing the quartet of bile acid transport deficiencies, as apical sodium-dependent bile acid transporter and bile salt export pump deficiencies were already known for years. Novel pathophysiological insights have been obtained from knockout mice lacking functional expression of these genes and from pharmacological transporter inhibition in mice or humans. Conclusion: We provide a concise overview of the four main bile salt transport pathways and of their status as possible targets of interventions in cholestatic or metabolic disorders.

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