scholarly journals Atp8b1 deficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile salts and impairs bile salt transport

Hepatology ◽  
2006 ◽  
Vol 44 (1) ◽  
pp. 195-204 ◽  
Author(s):  
Coen C. Paulusma ◽  
Annemiek Groen ◽  
Cindy Kunne ◽  
Kam S. Ho-Mok ◽  
Astrid L. Spijkerboer ◽  
...  
Keyword(s):  
Bile Salt ◽  
Bile Salts ◽  
Salt Transport ◽  
Canalicular Membrane ◽  
Bile Salt Transport

Electrogenicity of Na-coupled bile salt transport in isolated rat hepatocytes

1993 ◽  
Vol 265 (1) ◽  
pp. G73-G80
Author(s):  
S. A. Weinman ◽  
R. P. Weeks
Keyword(s):  
Bile Salt ◽  
Bile Salts ◽  
Input Resistance ◽  
Rat Hepatocytes ◽  
Salt Transport ◽  
Isolated Rat Hepatocytes ◽  
Voltage Change ◽  
Uptake Rates ◽  
Dependent Transport ◽  
Bile Salt Transport

The importance of membrane voltage in uptake of bile salts into hepatocytes is not known. Electrogenicity of the primary bile salt transport process, Na-bile salt cotransport, has been difficult to determine because the large K and Cl conductances of the sinusoidal membrane (GK and GCl, respectively) obscure any transport associated currents. In the present study hepatocytes were treated to reduce these membrane conductances and electrogenic entry of taurocholate and glycocholate was demonstrated. Intracellular voltage and resistance changes resulting from bile salt transport were measured in hepatocytes in which GK and GCl were blocked by impalement with Na acetate microelectrodes and external exposure to quinine (400 microM). This increased the cell input resistance from 153 +/- 17 to 230 +/- 17 M omega (n = 14, P < 0.001). Under these conditions, exposure to 100 microM of taurocholate or glycocholate produced Na-dependent depolarizations of 3.0 +/- 0.5 and 4.2 +/- 0.8 mV, respectively. These correspond to transport currents of 13.9 and 7.6 pA/cell, which are comparable to those predicted from known [3H]taurocholate uptake rates if one positive charge enters the cell with each bile salt molecule. Although uptake of these two bile salts was electrogenic, this was not the case for all bile salts. Na-dependent transport of taurodehydrocholate, which occurs at similar rates to that for taurocholate, produced no voltage change. The unconjugated bile salts cholate and ursodeoxycholate also produced no measurable voltage or resistance changes. In conclusion, Na-dependent uptake of taurocholate and glycocholate is electrogenic, whereas uptake of taurodehydrocholate, ursodeoxycholate, and cholate is predominantly electroneutral.(ABSTRACT TRUNCATED AT 250 WORDS)

Bile Salt Transporters: Molecular Characterization, Function, and Regulation

2003 ◽  
Vol 83 (2) ◽  
pp. 633-671 ◽  
Author(s):  
Michael Trauner ◽  
James L. Boyer
Keyword(s):  
Bile Salt ◽  
Molecular Characterization ◽  
Bile Salts ◽  
Organic Anion ◽  
Transport Proteins ◽  
Salt Transport ◽  
Transport Systems ◽  
Cholestatic Liver Disease ◽  
Bile Salt Transporters ◽  
Bile Salt Transport

Molecular medicine has led to rapid advances in the characterization of hepatobiliary transport systems that determine the uptake and excretion of bile salts and other biliary constituents in the liver and extrahepatic tissues. The bile salt pool undergoes an enterohepatic circulation that is regulated by distinct bile salt transport proteins, including the canalicular bile salt export pump BSEP (ABCB11), the ileal Na+-dependent bile salt transporter ISBT (SLC10A2), and the hepatic sinusoidal Na+- taurocholate cotransporting polypeptide NTCP (SLC10A1). Other bile salt transporters include the organic anion transporting polypeptides OATPs (SLC21A) and the multidrug resistance-associated proteins 2 and 3 MRP2,3 (ABCC2,3). Bile salt transporters are also present in cholangiocytes, the renal proximal tubule, and the placenta. Expression of these transport proteins is regulated by both transcriptional and posttranscriptional events, with the former involving nuclear hormone receptors where bile salts function as specific ligands. During bile secretory failure (cholestasis), bile salt transport proteins undergo adaptive responses that serve to protect the liver from bile salt retention and which facilitate extrahepatic routes of bile salt excretion. This review is a comprehensive summary of current knowledge of the molecular characterization, function, and regulation of bile salt transporters in normal physiology and in cholestatic liver disease and liver regeneration.

Bile salt excretion in skate liver is mediated by a functional analog of Bsep/Spgp, the bile salt export pump

2000 ◽  
Vol 278 (1) ◽  
pp. G57-G63 ◽  
Author(s):  
Nazzareno Ballatori ◽  
James F. Rebbeor ◽  
Gregory C. Connolly ◽  
David J. Seward ◽  
Benjamin E. Lenth ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Bile Salt ◽  
Rat Liver ◽  
Bile Salts ◽  
Plasma Membranes ◽  
Functional Characterization ◽  
Salt Transport ◽  
Positive Staining ◽  
Transport Activity ◽  
Canalicular Membrane

Biliary secretion of bile salts in mammals is mediated in part by the liver-specific ATP-dependent canalicular membrane protein Bsep/Spgp, a member of the ATP-binding cassette superfamily. We examined whether a similar transport activity exists in the liver of the evolutionarily primitive marine fish Raja erinacea, the little skate, which synthesizes mainly sulfated bile alcohols rather than bile salts. Western blot analysis of skate liver plasma membranes using antiserum raised against rat liver Bsep/Spgp demonstrated a dominant protein band with an apparent molecular mass of 210 kDa, a size larger than that in rat liver canalicular membranes, ∼160 kDa. Immunofluorescent localization with anti-Bsep/Spgp in isolated, polarized skate hepatocyte clusters revealed positive staining of the bile canaliculi, consistent with its selective apical localization in mammalian liver. Functional characterization of putative ATP-dependent canalicular bile salt transport activity was assessed in skate liver plasma membrane vesicles, with [3H]taurocholate as the substrate. [3H]taurocholate uptake into the vesicles was mediated by ATP-dependent and -independent mechanisms. The ATP-dependent component was saturable, with a Michaelis-Menten constant ( K m) for taurocholate of 40 ± 7 μM and a K m for ATP of 0.6 ± 0.1 mM, and was competitively inhibited by scymnol sulfate (inhibition constant of 23 μM), the major bile salt in skate bile. ATP-dependent uptake of taurocholate into vesicles was inhibited by known substrates and inhibitors of Bsep/Spgp, including other bile salts and bile salt derivatives, but not by inhibitors of the multidrug resistance protein-1 or the canalicular multidrug resistance-associated protein, indicating a distinct transport mechanism. These findings provide functional and structural evidence for a Bsep/Spgp-like protein in the canalicular membrane of the skate liver. This transporter is expressed early in vertebrate evolution and transports both bile salts and bile alcohols.

Molecular mechanisms of hepatic bile salt transport from sinusoidal blood into bile

1995 ◽  
Vol 269 (6) ◽  
pp. G801-G812 ◽  
Author(s):  
P. J. Meier
Keyword(s):  
Plasma Membrane ◽  
Bile Salt ◽  
Bile Salts ◽  
Organic Anion ◽  
Salt Transport ◽  
Salt Flux ◽  
Salt Uptake ◽  
Canalicular Bile ◽  
Salt Secretion ◽  
Bile Salt Transport

An increasingly complex picture has emerged in recent years regarding the bile salt transport polarity of hepatocytes. At the sinusoidal (or basolateral) plasma membrane two bile salt-transporting polypeptides have been cloned. The Na(+)-taurocholate-cotransporting polypeptide (Ntcp) can account for most, if not all, physiological properties of the Na(+)-dependent bile salt uptake function in mammalian hepatocytes. The cloned organic anion-transporting protein (Oatp1) can mediate Na(+)-independent transport of bile salts, sulfobromophthalein, estrogen conjugates, and a variety of other amphipathic cholephilic compounds. Hence, Oatp1 appears to correspond to the previously suggested basolateral multispecific bile sale transporter. Intracellular bile salt transport can be mediated by different pathways. Under basal bile salt flux conditions, conjugated trihydroxy bile salts bind to cytoplasmic binding proteins and reach the canalicular plasma membrane predominantly via cytoplasmic diffusion. More hydrophobic mono- and dihydroxy and high concentrations of trihydroxy bile salts associate with intracellular membrane-bound compartments, including transcytotic vesicles, endoplasmic reticulum (ER), and Golgi complex. A facilitated bile salt diffusion pathway has been demonstrated in the ER. The exact role of these and other (e.g., lysosomes, "tubulovesicular structures") organelles in overall vectorial transport of bile salts across hepatocytes is not yet known. Canalicular bile salt secretion is mediated by two ATP-dependent transport systems, one for monovalent bile salts and the second for divalent sulfated or glucuronidated bile salt conjugates. The latter is identical with the canalicular multispecific organic anion transporter, which also transports other divalent organic anions, such as glutathione S-conjugates. Potential dependent canalicular bile salt secretion has also been suggested to occur, but its exact mechanism and physiological significance remain unclear, since a potential driven bile salt uptake system has also been identified in the ER. Hypothetically, and similar to changes in cell volume, the intracellular potential could also play a role in the regulation of the number of bile salt carriers at the canalicular membrane and thereby indirectly influence the maximal canalicular bile salt transport capacity of hepatocytes.

Effects of sulfation patterns on intestinal transport of bile salt sulfate esters

1980 ◽  
Vol 238 (1) ◽  
pp. G34-G39 ◽  
Author(s):  
E. H. De Witt ◽  
L. Lack
Keyword(s):  
Bile Salt ◽  
Bile Salts ◽  
Intestinal Transport ◽  
Salt Transport ◽  
Adaptive Mechanism ◽  
Everted Gut Sac ◽  
Alpha 7 ◽  
Bile Salt Transport

The absorption of 14C-labeled 3 alpha-, the 7 alpha- and the 3 alpha,7 alpha-sulfate esters of taurochenodeoxycholate by guinea pig small intestine was studied using in vivo and in vitro preparations. In vivo ileal perfusions showed that sulfation markedly decreased uptake by the ileal bile salt transport system and that the position and number of the sulfate radicals affected the degree of transport inhibition. The following relationships were found: transport of taurochenodeoxycholate (TCDC) greater than TCDC-3-sulfate greater than TCDC-7 sulfate greater than TCDC-3,7-disulfate with a decrease of approximately 90% between each pair. In vitro, jejunal perfusions demonstrated that sulfation also decreased passive flux. By use of an everted gut sac technique, the ability of ileum to move the sulfated bile salts against a concentration gradient was measured. Under these conditions transport of TCDC-3-sulfate was minimal, and that of the 7-sulfate and 3,7-disulfate was not observed. In view of the reported increased levels of sulfated bile salts after total or partial biliary tract obstruction, our results support the concept of sulfation as an adaptive mechanism for enhancing fecal elimination of bile salts.

Bile salt transport in intestinal lymph of the rat

1982 ◽  
Vol 12 (1) ◽  
pp. 23-27 ◽  
Author(s):  
GEOFFREY J. BECKETT ◽  
IAIN W. PERCY-ROBB
Keyword(s):  
Bile Salt ◽  
Salt Transport ◽  
Intestinal Lymph ◽  
Bile Salt Transport

Hepatic bile flow

1984 ◽  
Vol 64 (4) ◽  
pp. 1055-1102 ◽  
Author(s):  
R. C. Strange
Keyword(s):  
Bile Salt ◽  
Bile Salts ◽  
Basolateral Membrane ◽  
Membrane Vesicles ◽  
Critical Micellar Concentration ◽  
Canalicular Membrane ◽  
Receptor Proteins ◽  
Subcellular Organelles ◽  
Golgi Bodies ◽  
Initial Event

The hepatocyte is a polar cell that can remove a variety of molecules from blood and excrete them into bile. This review is primarily concerned with the mechanism of transport of the principal anions--the bile salts--across the sinusoidal membrane, their passage through the cell, and excretion across the canalicular membrane. Clearly much of this process is poorly understood, but the study of the membrane stages should be facilitated by the ability to prepare purified sinusoidal and canalicular membrane vesicles. For example, the relative importance of albumin-binding sites as well as the putative bile salt receptor proteins can be better assessed. It seems likely that although the interaction of bile salts with receptor proteins is important, it is an initial event that puts the bile salt in the correct place for uptake to occur. The driving force for uptake is the Na+ gradient created across the basolateral membrane by the activity of the Na+-K+-ATPase. Within the cell, various modes of transport have been suggested. Several authors emphasize the importance of protein binding of bile salts, either because of their presumed ability to maintain the concentration of these anions in the hepatocyte below their critical micellar concentration or because of their putative role in transport. It is important to understand these aspects of the role of cytosolic proteins for several reasons. Knowledge of the true concentration of free bile salt within the cell should allow estimation of whether the electrochemical gradient is sufficient for bile salts to accumulate in bile without the need for active transport of molecules from the cell into the canaliculus. The compartmental model described by Strange et al. (153) offers one theoretical way of determining the concentration of free bile salt, although the problems inherent in studying amphipath binding to the membranes of subcellular organelles (31) require that the model be reevaluated by the hygroscopic-desorption method. The second role suggested for the cytosolic bile salt-binding proteins is as transport proteins. As discussed in section VI, I think it is unlikely that the proteins identified so far act in this way, and it is more likely that movement occurs by diffusion in free solution. It is also important to determine the possible involvement of subcellular organelles such as Golgi bodies. Little is known of their role in the transport of bile salts or indeed where bile salt micelles are formed.(ABSTRACT TRUNCATED AT 400 WORDS)

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