Assessment of biliary bicarbonate secretion in humans by positron emission tomography

Prìeto, Jesús; Garcı́a, Nicolás; Martí-Climent, Josep M.; Peñuelas, Iván; Richter, José; Medina, Juan F.

doi:10.1016/s0016-5085(99)70564-0

Cited by 128 publications

(94 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[17][18][19][20]39,43 Our data may provide a missing pathophysiologic link in the pathogenesis of PBC, which, in our view, is based on the interplay between genetic, exogenous, and endogenous predisposing factors. [17][18][19][20]39,43 Future therapeutic approaches might, therefore, aim to further strengthen the weakened biliary HCO À 3 umbrella in PBC. 7 Advances have been made in understanding the mechanisms and sites of action of ursodeoxycholic acid (UDCA) in the therapy of chronic cholangiopathies.…”

Section: Discussionmentioning

confidence: 78%

“…23 Ischemia-type biliary lesions and nonanastomotic bile duct strictures after liver transplantation with denervation in man 42 may be a consequence of disrupted vagal acetylcholine signaling, a physiologic driving force of biliary HCO À Our data may have particular impact on the understanding of the pathogenesis and treatment of PBC. [17][18][19][20]39,43 Increasing evidence supports the view that cholangiocyte apoptosis is a driving force in the pathogenesis of PBC: It has long been demonstrated that cholangiocyte apoptosis is associated with ductular inflammation in PBC, but not PSC. 44 Furthermore, cholangiocytes of small bile ducts expose immunologically reactive PDC-E2 or PDC-E2-like protein during apoptosis, 16 which might explain, in part, the organ specificity of the immune reaction in PBC.…”

Section: Discussionmentioning

confidence: 93%

“…15,16 By altering sensitivity toward bile salt toxicity and increasing frequency of apoptotic events in cholangiocytes, genetic and acquired defects disrupting the biliary HCO À 3 umbrella may be a common pathogenetic factor in various cholangiopathies. Genetic variants of key modulators of the biliary HCO À 3 umbrella 7 have been associated with the manifestation or progression of chronic cholestasis, as demonstrated for anion exchanger 2 (AE2) in PBC, [17][18][19][20] TGR5 in primary sclerosing cholangitis (PSC), 21 or cystic fibrosis transmembrane conductance regulator (CFTR) 22,23 in cystic-fibrosis-associated liver disease.…”

mentioning

confidence: 99%

See 2 more Smart Citations

A biliary HCO₃⁻umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes

et al. 2011

View full text Add to dashboard Cite

Human cholangiocytes are continuously exposed to millimolar levels of hydrophobic bile salt monomers. We recently hypothesized that an apical biliary HCO À 3 umbrella might prevent the protonation of biliary glycine-conjugated bile salts and uncontrolled cell entry of the corresponding bile acids, and that defects in this biliary HCO À 3 umbrella might predispose to chronic cholangiopathies. Here, we tested in vitro whether human cholangiocyte integrity in the presence of millimolar bile salt monomers is dependent on (1) pH, (2) adequate expression of the key HCO À 3 exporter, anion exchanger 2 (AE2), and (3) an intact cholangiocyte glycocalyx. To address these questions, human immortalized cholangiocytes and cholangiocarcinoma cells were exposed to chenodeoxycholate and its glycine/taurine conjugates at different pH levels. Bile acid uptake was determined radiochemically. Cell viability and apoptosis were measured enzymatically. AE2 was knocked down by lentiviral short hairpin RNA. A cholangiocyte glycocalyx was identified by electron microscopy, was enzymatically desialylated, and sialylation was quantified by flow cytometry. We found that bile acid uptake and toxicity in human immortalized cholangiocytes and cholangiocarcinoma cell lines in vitro were pH and AE2 dependent, with the highest rates at low pH and when AE2 expression was defective. An apical glycocalyx was identified on cholangiocytes in vitro by electron microscopic techniques. Desialylation of this protective layer increased cholangiocellular vulnerability in a pH-dependent manner. Conclusion: A biliary HCO À 3 umbrella protects human cholangiocytes against damage by bile acid monomers. An intact glycocalyx and adequate AE2 expression are crucial in this process. Defects of the biliary HCO À 3 umbrella may lead to the development of chronic cholangiopathies.

show abstract

Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 93%

mentioning

confidence: 99%

See 1 more Smart Citation

A biliary HCO₃⁻umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes

et al. 2011

View full text Add to dashboard Cite

show abstract

“…TUDCA, taken up into the hepatocyte by the Na ϩ -taurocholate cotransporting polypeptide (Ntcp), stimulates apical vesicular exocytosis and insertion of key canalicular transporters such as the conjugate export pump, Mrp2, and the bile salt export pump, Bsep, via Ca 2ϩ -and PKC␣-dependent mechanisms 15,17 or via activation of p38 MAPK and Ras-, Raf-, Erk-1/2-dependent mechanisms 24 33 Interestingly, anion exchanger 2 expression and bicarbonate secretion are impaired in patients with PBC and are up-regulated after treatment with UDCA. 34,35 Thus, stimulation of cholangiocellular HCO 3 Ϫ secretion may contribute to the anticholestatic effect of UDCA at least in certain biliary diseases in which HCO 3 Ϫ secretion is impaired.…”

Section: Stimulation Of Hepatobiliary Secretionmentioning

confidence: 99%

Ursodeoxycholic acid in cholestatic liver disease: Mechanisms of action and therapeutic use revisited

Paumgartner¹

2002

Hepatology

649

387

View full text Add to dashboard Cite

“…[1][2][3][4][5][6][7] Its interaction with a G-protein-coupled receptor selectively localized to the epithelial bile duct cells 8 results in increased intracellular levels of cyclic adenosine monophosphate (cAMP) [cAMP] i 7,9,10 and protein kinase A activation. 11,12 Phosphorylation and opening of a cAMP-dependent Cl Ϫ channel, the cystic fibrosis transmembrane conductance regulator (CFTR), 13 causes Cl Ϫ efflux to the ductular lumen.…”

mentioning

confidence: 99%

Bicarbonate-rich choleresis induced by secretin in normal rat is taurocholate-dependent and involves AE2 anion exchanger

et al. 2006

Self Cite

View full text Add to dashboard Cite

Canalicular bile is modified along bile ducts through reabsorptive and secretory processes regulated by nerves, bile salts, and hormones such as secretin. Secretin stimulates ductular cystic fibrosis transmembrane conductance regulator (CFTR)-dependent Cl ؊ efflux and subsequent biliary HCO 3 ؊ secretion, possibly via Cl ؊ /HCO 3 ؊ anion exchange (AE). However, the contribution of secretin to bile regulation in the normal rat, the significance of choleretic bile salts in secretin effects, and the role of Cl ؊ /HCO 3 ؊ exchange in secretin-stimulated HCO 3 ؊ secretion all remain unclear. Here, secretin was administered to normal rats with maintained bile acid pool via continuous taurocholate infusion. Bile flow and biliary HCO 3 ؊ and Cl ؊ excretion were monitored following intrabiliary retrograde fluxes of saline solutions with and without the Cl ؊ channel inhibitor 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) or the Cl ؊ /HCO 3 ؊ exchange inhibitor 4,4 -diisothiocyanatostilbene-2,2 -disulfonic acid (DIDS). Secretin increased bile flow and biliary excretion of HCO 3 ؊ and Cl ؊ . Interestingly, secretin effects were not observed in the absence of taurocholate. Whereas secretin effects were all blocked by intrabiliary NPPB, DIDS only inhibited secretin-induced increases in bile flow and HCO 3 ؊ excretion but not the increased Cl ؊ excretion, revealing a role of biliary Cl ؊ /HCO 3 ؊ exchange in secretininduced, bicarbonate-rich choleresis in normal rats. Finally, small hairpin RNA adenoviral constructs were used to demonstrate the involvement of the Na ؉ -independent anion exchanger 2 (AE2) through gene silencing in normal rat cholangiocytes. AE2 gene silencing caused a marked inhibition of unstimulated and secretin-stimulated Cl ؊ /HCO 3 ؊ exchange. In conclusion, maintenance of the bile acid pool is crucial for secretin to induce bicarbonate-rich choleresis in the normal rat and that this occurs via a chloride-bicarbonate exchange process consistent with AE2 function. (HEPATOLOGY 2006;43:266-275.) S ecretin is known to induce bicarbonate-rich hydrocholeresis in many animal species. 1-7 Its interaction with a G-protein-coupled receptor selectively localized to the epithelial bile duct cells 8 results in increased intracellular levels of cyclic adenosine monophosphate (cAMP) [cAMP] i 7,9,10 and protein kinase A activation. 11,12 Phosphorylation and opening of a cAMP-dependent Cl Ϫ channel, the cystic fibrosis transmembrane conductance regulator (CFTR), 13 causes Cl Ϫ efflux to the ductular lumen. This appears to stimulate an apical Na ϩ -independent Cl Ϫ /HCO 3 Ϫ anion exchange (AE), 14 with HCO 3 Ϫ efflux and Cl Ϫ influx, that is facilitated by the outside to inside transmembrane gradient of Cl Ϫ at relatively high intracellular HCO 3 Ϫ concentration. [10][11][12]15,16 Several bicarbonate transporters, most of them encoded by the SLC4 and SLC26 gene families, 17 have been described to exert AE activity. A decade ago, we localized one of those polypeptides, the SLC4A2 or AE2, 18 to the apical membrane in...

show abstract

Assessment of biliary bicarbonate secretion in humans by positron emission tomography

Cited by 128 publications

References 13 publications

A biliary HCO₃⁻umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes

A biliary HCO₃⁻umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes

Ursodeoxycholic acid in cholestatic liver disease: Mechanisms of action and therapeutic use revisited

Bicarbonate-rich choleresis induced by secretin in normal rat is taurocholate-dependent and involves AE2 anion exchanger

Contact Info

Product

Resources

About

Assessment of biliary bicarbonate secretion in humans by positron emission tomography

Cited by 128 publications

References 13 publications

A biliary HCO3−umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes

A biliary HCO3−umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes

Ursodeoxycholic acid in cholestatic liver disease: Mechanisms of action and therapeutic use revisited

Bicarbonate-rich choleresis induced by secretin in normal rat is taurocholate-dependent and involves AE2 anion exchanger

Contact Info

Product

Resources

About

A biliary HCO₃⁻umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes

A biliary HCO₃⁻umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes