The Bile Salt Export Pump

Department of Medicine, Institute of Clinical Pharmacology and Toxicology, University Hospital, Zürich, Switzerland.
Pflügers Archiv - European Journal of Physiology (Impact Factor: 4.1). 03/2007; 453(5):611-20. DOI: 10.1007/s00424-006-0152-8
Source: PubMed

ABSTRACT Canalicular secretion of bile salts mediated by the bile salt export pump Bsep constitutes the major driving force for the generation of bile flow. Bsep is a member of the B-family of the super family of ATP-binding cassette transporters and is classified as ABCB11. Bsep has a narrow substrate specificity, which is largely restricted to bile salts. Bsep is extensively regulated at the transcriptional and posttranscriptional level, which directly modulates canalicular bile formation. Pathophysiological alterations of Bsep by either inherited mutations or acquired processes such as inhibition by drugs or disease-related down regulation may lead to a wide spectrum of mild to severe forms of liver disease. Furthermore, many genetic variants of Bsep are known, some of which potentially render individuals susceptible to acquired forms of liver disease.

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    • "Intra-hepatic cholestasis represents a frequent manifestation of DILI in humans (Lee, 2003). In many cases, it results from alterations of the hepatobiliary transporter system, in particular the bile salt export pump (BSEP), which is the most physiologically important canalicular bile transporter (Stieger et al., 2007). Other disturbances, such as altered cell polarity, disruption of cell-to-cell junctions and cytoskeleton disorganization, can also participate in cholestasis. "
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    ABSTRACT: Mechanisms involved in drug-induced cholestasis in humans remain poorly understood. Although cyclosporine A (CsA) and tacrolimus (FK506) share similar immunosuppressive properties, only CsA is known to cause dose-dependent cholestasis. Here, we have investigated the mechanisms implicated in early cholestatic effects of CsA using the differentiated human HepaRG cell line. Inhibition of efflux and uptake of taurocholate was evidenced as early as 15 minutes and 1 hour respectively after addition of 10 μM CsA; it peaked at around 2 hours and was reversible. These early effects were associated with generation of oxidative stress and deregulation of cPKC pathway. At higher CsA concentrations (≥50 μM) alterations of efflux and uptake activities were enhanced and became irreversible, pericanalicular F-actin microfilaments were disorganized and bile canaliculi were constricted. These changes were associated with induction of endoplasmic reticulum stress that preceded generation of oxidative stress. Concentration-dependent changes were observed on total bile acid disposition, which were characterized by an increase and a decrease in culture medium and cells respectively, after a 24-hour treatment with CsA. Accordingly, genes encoding hepatobiliary transporters and bile acid synthesis enzymes were differently deregulated depending on CsA concentration. By contrast, FK506 induced limited effects only at 25-50 μM and did not alter bile canaliculi. Our data demonstrate involvement of different concentration-dependent mechanisms in CsA-induced cholestasis and point out a critical role of endoplasmic reticulum stress in the occurrence of the major cholestatic features.
    Toxicological Sciences 06/2014; DOI:10.1093/toxsci/kfu122 · 3.85 Impact Factor
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    • "Later studies revealed additional ABCB transporters as MDR proteins. Besides xenobiotic extrusion (ABCB1, 5, 8) [72]–[74], ABCB members are also known in human biology for the translocation, for example, of phosphatidylcholine (ABCB4) [75], bile acids (ABCB11) [76], peptides (TAP1:TAP2 (antigen processing in the adaptive immune system), TAPL, mitochondrial ABCB10) [77], metabolites of the heme synthetic pathway (ABCB6) [78], or iron (mitochondrial ABCB7 and 8) [79]–[82]. In insects, several examples suggest the involvement of P-glycoproteins in the resistance to insecticides used for crop protection [23], [24], [83]–[91]. "
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    ABSTRACT: Background Insects evolved ingenious adaptations to use extraordinary food sources. Particularly, the diet of herbivores enriched with noxious plant secondary metabolites requires detoxification mechanisms. Sequestration, which involves the uptake, transfer, and concentration of occasionally modified phytochemicals into specialized tissues or hemolymph, is one of the most successful detoxification strategies found in most insect orders. Due to the ability of ATP-binding cassette (ABC) carriers to transport a wide range of molecules including phytochemicals and xenobiotics, it is highly likely that they play a role in this sequestration process. To shed light on the role of ABC proteins in sequestration, we describe an inventory of putative ABC transporters in various tissues in the sequestering juvenile poplar leaf beetle, Chrysomela populi. Results In the transcriptome of C. populi, we predicted 65 ABC transporters. To link the proteins with a possible function, we performed comparative phylogenetic analyses with ABC transporters of other insects and of humans. While tissue-specific profiling of each ABC transporter subfamily suggests that ABCB, C and G influence the plant metabolite absorption in the gut, ABCC with 14 members is the preferred subfamily responsible for the excretion of these metabolites via Malpighian tubules. Moreover, salicin, which is sequestered from poplar plants, is translocated into the defensive glands for further deterrent production. In these glands and among all identified ABC transporters, an exceptionally high transcript level was observed only for Cpabc35 (Cpmrp). RNAi revealed the deficiency of other ABC pumps to compensate the function of CpABC35, demonstrating its key role during sequestration. Conclusion We provide the first comprehensive phylogenetic study of the ABC family in a phytophagous beetle species. RNA-seq data from different larval tissues propose the importance of ABC pumps to achieve a homeostasis of plant-derived compounds and offer a basis for future analyses of their physiological function in sequestration processes.
    PLoS ONE 06/2014; 9(6):e98637. DOI:10.1371/journal.pone.0098637 · 3.23 Impact Factor
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    • "For male adults to excrete pheromones, transporters need to provide mechanisms for the bile salts to exit hepatocytes as well as to enter and to exit gill epithelial cells. Expression of bsep, which encodes for an ATP-dependent bile salt export pump (BSEP) that is known for secretions of bile salts out of the hepatocytes [25], remained substantially high in the liver of both maturation states. As expected, the bsep mRNA level specifically increased in the lamprey liver from IM to SM, corresponding with the up-regulation of bile salt synthesis seen in SMs. "
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    ABSTRACT: In vertebrates, bile salts are primarily synthesized in the liver and secreted into the intestine where they aid in absorption of dietary fats. Small amounts of bile salts that are not reabsorbed into enterohepatic circulation are excreted with waste. In sexually mature male sea lamprey (Petromyzon marinus L.) a bile salt is released in large amounts across gill epithelia into water where it functions as a pheromone. We postulate that the release of this pheromone is associated with a dramatic increase in its biosynthesis and transport to the gills upon sexual maturation. We show an 8000-fold increase in transcription of cyp7a1, a three-fold increase in transcription of cyp27a1, and a six-fold increase in transcription of cyp8b1 in the liver of mature male sea lamprey over immature male adults. LC--MS/MS data on tissue-specific distribution and release rates of bile salts from mature males show a high concentration of petromyzonol sulfate (PZS) in the liver and gills of mature males. 3-keto petromyzonol sulfate (3kPZS, known as a male sex pheromone) is the primary compound released from gills, suggesting a conversion of PZS to 3kPZS in the gill epithelium. The PZS to 3kPZS conversion is supported by greater expression of hsd3b7 in gill epithelium. High expression of sult2b1 and sult2a1 in gill epithelia of mature males, and tissue-specific expression of bile salt transporters such as bsep, slc10a1, and slc10a2, suggest additional sulfation and transport of bile salts that are dependent upon maturation state. This report presents a rare example where specific genes associated with biosynthesis and release of a sexual pheromone are dramatically upregulated upon sexual maturation in a vertebrate. We provide a well characterized example of a complex mechanism of bile salt biosynthesis and excretion that has likely evolved for an additional function of bile salts as a mating pheromone.
    BMC Biochemistry 11/2013; 14(1):30. DOI:10.1186/1471-2091-14-30 · 1.44 Impact Factor
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