OST alpha-OST beta: a key membrane transporter of bile acids and conjugated steroids

Ballatori, Nazzareno; Li, Na; Fang, Fang; Boyer, James L.; Christian, Whitney V.; Hammond, Christine L.

doi:10.2741/3416

Cited by 101 publications

(81 citation statements)

References 100 publications

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“…Current concepts assume mechanisms that would limit intracellular accumulation of potentially toxic bile salts under cholestatic conditions. 17,28,32 This includes down-regulation of Ntcp 33 or OATPs 34 at the basolateral membrane in order to limit bile salt uptake, or upregulation of Mrp4, 34 Mrp3, 35 and OSTa/b, 12 which may enhance bile salt secretion back into the systemic circulation. Bile salt inflow to the liver may increase considerably under pathophysiological conditions, but may also reach physiological concentrations of up to 150 lmol/L (in rat).…”

Section: Discussionmentioning

confidence: 99%

“…9 Furthermore, bile salt export back into the blood may also occur at the sinusoidal membrane and may be mediated by Mrp3 (ABCC3) and Mrp4 (ABCC4), two members of the ABC subfamily C, as well as the organic solute transporter OST a/b. [10][11][12] Rat Ntcp is an integral membrane glycoprotein with putative seven transmembrane domains. On a long-term scale bile salts down-regulate Ntcp at the level of gene transcription, which is mediated by the farnesoid-X-receptor (FXR) and the short heterodimer partner 1 (SHP1).…”

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confidence: 99%

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Short-term feedback regulation of bile salt uptake by bile salts in rodent liver

et al. 2012

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The sodium taurocholate cotransporting polypeptide (Ntcp) is the major bile salt uptake transporter at the sinusoidal membrane of hepatocytes. Short-term feedback regulation of Ntcp by primary bile salts has not yet been investigated in vivo. Subcellular localization of Ntcp was analyzed in Ntcp-transfected HepG2-cells by flow cytometry and in immunofluorescence images from tissue sections by a new automated image analysis method. Net bile salt uptake was investigated in perfused rat liver by a pulse chase technique. In Flag-Ntcp-EGFP (enhanced green fluorescent protein) expressing HepG2-cells, taurochenodeoxycholate (TCDC), but not taurocholate (TC), induced endocytosis of Ntcp. TCDC, but not TC, caused significant internalization of Ntcp in perfused rat livers, as shown by an increase in intracellular Ntcp immunoreactivity, whereas Bsep distribution remained unchanged. These results correlate with functional studies. Rat livers were continuously perfused with 100 mu mol/L of TC. 25 mu mol/L of TCDC, taurodeoxycholate (TDC), tauroursodeoxycholate (TUDC), or TC were added for 30 minutes, washed out, followed by a pulse of (3)[H]-TC. TCDC, but not TDC, TUDC, or TC significantly increased the amount of (3)[H]-TC in the effluent, indicating a reduced sinusoidal net TC uptake. This effect was sensitive to chelerythrine (protein kinase C inhibitor) and cypermethrin (protein phosphatase 2B inhibitor). Phosphoinositide 3-kinase (PI3K) inhibitors had an additive effect, whereas Erk1/2 (extracellular signal activated kinase 1/2), p38MAPK, protein phosphatase 1/2A (PP1/2A), and reactive oxygen species (ROS) were not involved. Conclusion: TCDC regulates bile salt transport at the sinusoidal membrane by protein kinase C-and protein phosphatase 2B-mediated retrieval of Ntcp from the plasma membrane. During increased portal bile salt load this mechanism may adjust bile salt uptake along the acinus and protect periportal hepatocytes from harmful bile salt concentrations

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Short-term feedback regulation of bile salt uptake by bile salts in rodent liver

et al. 2012

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“…In reality, the pharmacokinetic-absorption-distribution-metabolism-excretiontoxicity (PK-ADME-TOX) profiles of individual BAs are complex and must be viewed in light of their EHR (Ballatori et al, 2009;Gonzalez, 2012), renal clearance, vectorial flux by multiple transporters, transport out of cells back into blood, 3-O-sulfation, glucuronidation, amidation, and the nuclear hormone receptor (NHR)-mediated "adaptive" responses of the liver, kidney, and intestine ( Fig. 2B; liver shown).…”

Section: Introductionmentioning

confidence: 99%

Drug-Induced Perturbations of the Bile Acid Pool, Cholestasis, and Hepatotoxicity: Mechanistic Considerations beyond the Direct Inhibition of the Bile Salt Export Pump

et al. 2013

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The bile salt export pump (BSEP) is located on the canalicular plasma membrane of hepatocytes and plays an important role in the biliary clearance of bile acids (BAs). Therefore, any drug or new chemical entity that inhibits BSEP has the potential to cause cholestasis and possibly liver injury. In reality, however, one must consider the complexity of the BA pool, BA enterohepatic recirculation (EHR), extrahepatic (renal) BA clearance, and the interplay of multiple participant transporters and enzymes (e.g., sulfotransferase 2A1, multidrug resistance-associated protein 2, 3, and 4). Moreover, BAs undergo extensive enzyme-catalyzed amidation and are subjected to metabolism by enterobacteria during EHR. Expression of the various enzymes and transporters described above is governed by nuclear hormone receptors (NHRs) that mount an adaptive response when intracellular levels of BAs are increased. The intracellular trafficking of transporters, and their ability to mediate the vectorial transport of BAs, is governed by specific kinases also. Finally, bile flow, micelle formation, canalicular membrane integrity, and BA clearance can be influenced by the inhibition of multidrug resistant protein 3-or ATPase-aminophospholipid transporter-mediated phospholipid flux. Consequently, when screening compounds in a discovery setting or conducting mechanistic studies to address clinical findings, one has to consider the direct (inhibitory) effect of the parent drug and metabolites on multiple BA transporters, as well as inhibition of BA sulfation and amidation and NHR function. Vectorial BA transport, in addition to BA EHR and homoeostasis, could also be impacted by drug-dependent modulation of kinases and enterobacteria.

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“…These include t-ASBT, multidrug resistance protein 3 (MRP3/ ABCB4), MRP4, organic anion transporting polypeptide 3 (Oatp3), and the organic solute transporter Ost alpha-Ost beta (25,28,36,119,158), the lattermost of which appears to play a central role in this process (25,28).…”

Section: Cholangiocyte Absorptionmentioning

confidence: 99%

Physiology of Cholangiocytes

Masyuk¹,

Masyuk²,

LaRusso³

2012

Physiology of the Gastrointestinal Tract

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Cholangiocytes are epithelial cells that line the intra-and extrahepatic ducts of the biliary tree. The main physiologic function of cholangiocytes is modification of hepatocyte-derived bile, an intricate process regulated by hormones, peptides, nucleotides, neurotransmitters, and other molecules through intracellular signaling pathways and cascades. The mechanisms and regulation of bile modification are reviewed herein.

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OST alpha-OST beta: a key membrane transporter of bile acids and conjugated steroids

Cited by 101 publications

References 100 publications

Short-term feedback regulation of bile salt uptake by bile salts in rodent liver

Short-term feedback regulation of bile salt uptake by bile salts in rodent liver

Drug-Induced Perturbations of the Bile Acid Pool, Cholestasis, and Hepatotoxicity: Mechanistic Considerations beyond the Direct Inhibition of the Bile Salt Export Pump

Physiology of Cholangiocytes

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