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Query: UMLS:C0008370 (cholestasis)
 9,378 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transport processes responsible for bile flow are reviewed. Canalicular bile acid-dependent flow is the result of active transport of bile acids by the hepatocyte into bile canaliculi. Bile acids are taken up by at least two transport systems whose mRNA have been expressed in Xenopus oocytes: (i) a Na(+)-dependent system, named NTCP, and (ii) a Na(+)- independent system, named OATP. Bile acids are then secreted into bile by two other transport systems, an ATP-dependent system and an 'electrogenic' voltage-dependent system. It is not known whether these two systems are mediated by the same protein or by two different proteins. Canalicular bile acid-independent flow is mainly the result of the secretion of glutathione into bile. The canalicular membrane also contains several proteins of the multi drug resistance (MDR) family. MDRI is responsible for biliary secretion of cationic drugs. MDR3 (mdr 2 in mice) plays a major role in the secretion of phospholipids. A third MDR-related protein has been shown recently to be the canalicular carrier of organic anions, such as bilirubin and dyes (the canalicular multiple organic anion transporter, or cMOAT). Biliary epithelial cells secrete a bicarbonate-rich solution, mostly in response to secretin. This secretion depends upon the presence, on the apical membrane of these cells of the CFTR, a chloride channel activated by cAMP and of a chloride/bicarbonate exchanger. Knowledge of these transport systems should allow a better understanding of the mechanisms involved in cholestasis.
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PMID:Review article: new insights into the mechanisms of hepatic transport and bile secretion. 879 13

The transport processes responsible for bile flow are reviewed. Canalicular bile acid-dependent flow is the result of active transport of bile acids by the hepatocyte into bile canaliculi. Bile acids are taken up by at least two transport systems whose mRNAs have been expressed in Xenopus oocytes: a Na(+)-dependent system, named NTCP, and a Na(+)-independent system, named OATP. Bile acids are then secreted into bile by two other transport systems, an ATP-dependent system and an "electrogenic" voltage-dependent system. It is not known whether these two systems are mediated by the same protein or by two different proteins. Canalicular bile acid-independent flow is mainly the result of the secretion of glutathione into bile. The canalicular membrane contains also several proteins of the MDR (Multi Drug Resistance) family. MDR1 is responsible for biliary secretion of cationic drugs. MDR2 plays a major role in the secretion of phospholipids. A third MDR related protein has been shown recently to be the canalicular carrier of organic anions, like bilirubin and dyes (the canalicular Multiple Organic Anion Transporter, or cMOAT). Biliary epithelial cells secrete a bicarbonate rich solution, mostly in response to secretion. This secretion depends on the presence on the apical membrane of these cells of the CFTR, a chloride channel activated by cAMP, and of a chloride/bicarbonate exchanger. Knowledge of these transport systems should allow a better understanding of the mechanisms involved in cholestasis.
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PMID:Mechanisms of hepatic transport and bile secretion. 890 66

Cholangiocytes, the epithelial cells that line intrahepatic bile ducts, participate in bile secretion via basal and agonist-stimulated transport of solutes and water. On the basis of subtle structural differences between cholangiocytes lining small vs. large bile ducts, as well as known phenotypic variations among transporting epithelia in other organs, we demonstrated that cholangiocytes are functionally heterogeneous along the intrahepatic biliary tree of normal rats. In studies reported here, we confirm and extend the concept of functional heterogeneity of cholangiocytes by employing the bile duct-ligated (BDL) rat model of cholestasis associated with selective cholangiocyte proliferation. Using novel isolation and separatory techniques, we prepared subpopulations of pure small, medium, and large cholangiocytes from BDL rats and compared them with regard to gene expression and basal or agonist-responsive transport activities. Although transcripts for gamma-glutamyl transpeptidase and cytokeratin 19, two cholangiocyte-specific proteins, and glyceraldehyde-3-phosphate dehydrogenase, a housekeeping gene, were in all three subpopulations, genes for several proteins involved in solute transport [Cl-/HCO3- exchanger, cystic fibrosis transmembrane conductance regulator (CFTR), and secretin receptor] were expressed only in medium and large cholangiocytes. Consistent with these findings, secretin increased intracellular levels of adenosine 3',5'-cyclic monophosphate (cAMP) and 36Cl- efflux rates in medium and large cholangiocytes but not in small cholangiocytes. Also, forskolin/8-(4-chlorophenylthio)-cAMP stimulated 36Cl- efflux rates only in medium and large cholangiocytes, consistent with selective functional expression of CFTR in these subpopulations. These results support the molecular and functional heterogeneity of cholangiocytes within the intrahepatic biliary ductal system and are consistent with the notion that hormone-regulated transport of solutes after BDL occurs principally in medium and large cholangiocytes in a fashion similar to that observed in normal rat liver.
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PMID:Molecular and functional heterogeneity of cholangiocytes from rat liver after bile duct ligation. 912 53

Accumulation of bile acids (BA) and cholangiocyte proliferation occur in cholestasis, but BA effects on the proliferative and secretory capacity of cholangiocytes are undefined. Cholangiocyte proliferation coupled with increased expression of H3 histone and secretin receptor (SR) genes and secretin-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) levels is limited to large cholangiocytes. We isolated pooled small and large cholangiocytes and studied the effect of taurocholic (TC) and taurolithocholic (TLC) acids on proliferation, by measurement of H3 histone gene expression, and secretion, by measurement of SR gene expression, cAMP levels, and Cl-/HCO3- exchanger activity. In pooled cholangiocytes, TC and TLC increased H3 histone (12-fold) and SR (3-fold) gene expression and both spontaneous (1.4-fold) and secretin-induced (4-fold) cAMP response. TC and TLC increased H3 histone (10-fold) and SR (2-fold) gene expression and secretin-induced cAMP response and Cl-/HCO3- exchanger activity (3-fold) only in large cholangiocytes. In large cholangiocytes, BA may have a signaling function in the modulation of ductal secretion.
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PMID:Bile acids stimulate proliferative and secretory events in large but not small cholangiocytes. 927 33

Formation of bile requires the coordinated function of two epithelial cell types: hepatocytes, that are responsible for secretion of the major osmolytes and biliary constituents and cholangiocytes that regulate the fluidity and alkalinity of bile through secretion of osmolytes such as Cl- and HCO3- Studies in isolated cholangiocyte preparations have elucidated the basic transport mechanisms involved in constitutive and stimulated secretory activities in the biliary epithelium. Basolateral Na+/H+ exchanger and Na+:HCO3- symporter mediate HCO3- uptake, while an apical cAMP-activated Cl-/HCO3- exchanger secretes bicarbonate into the lumen. Cholangiocytes also possess a cAMP-stimulated Cl- conductance (CFTR) and a Ca-activated Cl- channel, both likely located at the apical membrane. Cholangiocyte secretory functions are regulated by a complex network of hormones mainly acting via the cAMP system. In addition, recent data indicate that part of the regulation of ductular secretion may take place at the apical membrane of the cholangiocyte through factors present into the bile, such as ATP, bile acids and glutathione. Primary damage to the biliary epithelium is the cause of several chronic cholestatic disorders (cholangiopathies). From a pathophysiological point of view, common to all cholangiopathies is the coexistance of cholangiocyte death and proliferation and various degrees of portal inflammation and fibrosis. Cholestasis dominates the clinical picture and, pathophysiologically, may initiate or worsen the process. Alterations in biliary electrolyte transport could contribute to the pathogenesis of cholestasis in primary bile duct diseases. Cystic Fibrosis-related liver disease represents an example of biliary cirrhosis secondary to a derangement of cholangiocyte ion transport. Most primary cholangiopaties recognize an immune-mediated pathogenesis. Cytokines, chemokines, and proinflammatory mediators released in the portal spaces or produced by the cholangiocyte itself, likely activate fibrogenesis, stimulate apoptotic and proliferative responses, and alter the transport functions of the epithelium.
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PMID:Transport systems in cholangiocytes: their role in bile formation and cholestasis. 962 63

Cholestasis is a cardinal complication of liver disease, but most treatments are merely supportive. Here we report that the sulfonylurea glybenclamide potently stimulates bile flow and bicarbonate excretion in the isolated perfused rat liver. Video-microscopic studies of isolated hepatocyte couplets and isolated bile duct segments show that this stimulatory effect occurs at the level of the bile duct epithelium, rather than through hepatocytes. Measurements of cAMP, cytosolic pH, and Ca2+ in isolated bile duct cells suggest that glybenclamide directly activates Na+-K+-2Cl- cotransport, rather than other transporters or conventional second-messenger systems that link to secretory pathways in these cells. Finally, studies in livers from rats with endotoxin- or estrogen-induced cholestasis show that glybenclamide retains its stimulatory effects on bile flow and bicarbonate excretion even under these conditions. These findings suggest that bile duct epithelia may represent an important new therapeutic target for treatment of cholestatic disorders.
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PMID:Stimulation of bile duct epithelial secretion by glybenclamide in normal and cholestatic rat liver. 963

The regulation of cAMP synthesis by hormones and bile acids is altered in isolated hamster hepatocytes 2 days after bile duct ligation (BDL) [Y. Matsuzaki, B. Bouscarel, M. Le, S. Ceryak, T. W. Gettys, J. Shoda, and H. Fromm. Am. J. Physiol. 273 (Gastrointest. Liver Physiol. 36): G164-G174, 1997]. Therefore, studies were undertaken to elucidate the mechanism(s) responsible for this impaired modulation of cAMP formation. Hepatocytes were isolated 48 h after either a sham operation or BDL. Both preparations were equally devoid of cholangiocyte contamination. Although the basal cAMP level was not affected after BDL, the ability of glucagon to maximally stimulate cAMP synthesis was decreased by approximately 40%. This decreased glucagon effect after BDL was not due to alteration of the total glucagon receptor expression. However, this effect was associated with a parallel 50% decreased expression of the small stimulatory G protein alpha-subunit (GsalphaS). The expression of either the large subunit (GsalphaL) or the common beta-subunit remained unchanged. The expression of Gialpha2 and Gialpha3 was also decreased by 25 and 46%, respectively, and was associated with the failure of ANG II to inhibit stimulated cAMP formation. Therefore, alterations of the expression of GsalphaS and Galphai are, at least in part, responsible for the attenuated hormonal regulation of cAMP synthesis. Because cAMP has been reported to stimulate both bile acid uptake and secretion, impairment of cAMP synthesis and bile acid uptake may represent an initial hepatocellular defense mechanism during cholestasis.
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PMID:Changes in G protein expression account for impaired modulation of hepatic cAMP formation after BDL. 969 16

Cystic fibrosis (CF) is a lethal autosomal recessive genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR). Mutations in the CFTR gene may result in a defective processing of its protein and alter the function and regulation of this channel. Mutations are associated with different symptoms, including pancreatic insufficiency, bile duct obstruction, infertility in males, high sweat Cl-, intestinal obstruction, nasal polyp formation, chronic sinusitis, mucus dehydration, and chronic Pseudomonas aeruginosa and Staphylococcus aureus lung infection, responsible for 90% of the mortality of CF patients. The gene responsible for the cellular defect in CF was cloned in 1989 and its protein product CFTR is activated by an increase of intracellular cAMP. The CFTR contains two membrane domains, each with six transmembrane domain segments, two nucleotide-binding domains (NBDs), and a cytoplasmic domain. In this review we discuss the studies that have correlated the role of each CFTR domain in the protein function as a chloride channel and as a regulator of the outwardly rectifying Cl- channels (ORCCs).
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PMID:Structure and function of the cystic fibrosis transmembrane conductance regulator. 1045 65

The bile canaliculus contains at least four ATP-binding cassette (ABC) proteins responsible for ATP-dependent transport of bile acids (spgp), nonbile acid organic anions (mrp2), organic cations (mdr1), and phosphatidylcholine (mdr2). Other ABC transporters (including mrp3) have also been partially localized to the canaliculus; however, their function has not been fully delineated. The specific amount and function of spgp and mrp2 in the canalicular membrane increases in response to taurocholate and cAMP. The mechanism involves increased recruitment of spgp and mrp2 from Golgi to the canalicular membrane by a microtubular and PI3 kinase-dependent vesicular trafficking system. Because the effects of taurocholate and cAMP summate, two distinct pathways are proposed. Mdr family members traffic either directly to the apical plasma membrane or, in the case of spgp, through a separate intracellular pool(s); in either case, there is no direct evidence for transcytosis of ABC transporters from Golgi to basolateral plasma membrane and subsequently to the canalicular plasma membrane. Direct transfer from Golgi to apical membrane was demonstrated by in vivo pulse labeling, in vitro membrane localization, and on-line video microscopy in WIFB9 cells that were stably transfected with mdr1-GFP. A critical role for 3'-phosphoinositide products of PI3 kinase was demonstrated in the intracellular trafficking of canalicular ABC transporters and for optimal transporter activity within the canalicular membrane. These studies suggest that many intracellular components, including ATP, Ca2+, numerous GTPases, microtubules, cytoplasmic motors, and other unknown factors, are required for physiologic regulation of ABC transporter traffic from Golgi to the canalicular membrane. Defects in this complex system are postulated to produce an "intrahepatic traffic jam" that results in defective ABC transporter function in the canalicular membrane and, consequently, in cholestasis.
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PMID:Intracellular trafficking and regulation of canalicular ATP-binding cassette transporters. 1107

Hyperglycemia associated with obstructive jaundice seriously affects the prognosis of patients with hepatobiliary diseases. We investigated secretory properties of isolated islets from bile duct-ligated (BDL) rats. Pancreatic islets from BDL rats lost their secretory responses to glucagon-like peptide-1 (GLP-1), although their responses to glucose were normal. Loss of potentiation of insulin release was also observed in glucagon and glucose-dependent insulinotropic peptide (GIP), whereas modulation of the release by forskolin, dibutyryl cAMP, or epinephrine remained unaffected. cAMP production by BDL islets was not increased by these insulinotropic hormones. Serum levels of glucagon, but not GIP, were increased in BDL rats. GLP-1 levels were also elevated, although they did not reach statistical significance. Immunoblotting of trimeric G protein subunits demonstrated that G(s)alpha L and G(s)alpha S, but not G(i)alpha 1/2 and G(i)alpha 3/o alpha, were less expressed in BDL islets. Therefore, unresponsiveness of the beta-cell to cAMP-raising hormones is involved in glucose intolerance under cholestasis. It results from diminished expression of alpha-subunits of the relevant G protein, G(s), and desensitization of receptors of these hormones.
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PMID:Lack of effect of incretin hormones on insulin release from pancreatic islets in the bile duct-ligated rats. 1112 Jun 59


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