Bile acid and bile salt disrupt gastric mucosal barrier in the dog by different mechanisms

Duane, William; Wiegand, Dorothy M.; Sievert, Chester E.

doi:10.1152/ajpgi.1982.242.2.g95

Cited by 19 publications

(13 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1–2) [15], changes in biliary pH would have a minor, negligible effect on bile salt protonation and toxicity. pH dependency of cell penetration and toxicity by bile salts has been established in gastric and esophageal mucosa cells [16,17,18]. It was the aim of the present study to test the concept of pH dependency of bile salt-induced toxicity in human cholangiocytes and to explore the role of AE2 expression in the protection against hydrophobic bile salt-induced cholangiotoxicity.…”

Section: Introductionmentioning

confidence: 98%

Biliary Bicarbonate Secretion Constitutes a Protective Mechanism against Bile Acid- Induced Injury in Man

Hohenester

Wenniger

Jefferson

et al. 2011

Dig Dis

View full text Add to dashboard Cite

Background: Cholangiocytes expose a striking resistance against bile acids: while other cell types, such as hepatocytes, are susceptible to bile acid-induced toxicity and apoptosis already at micromolar concentrations, cholangiocytes are continuously exposed to millimolar concentrations as present in bile. We present a hypothesis suggesting that biliary secretion of HCO₃^– in man serves to protect cholangiocytes against bile acid-induced damage by fostering the deprotonation of apolar bile acids to more polar bile salts. Here, we tested if bile acid-induced toxicity is pH-dependent and if anion exchanger 2 (AE2) protects against bile acid-induced damage. Methods: A human cholangiocyte cell line was exposed to chenodeoxycholate (CDC), or its glycine conjugate, from 0.5 mM to 2.0 mM at pH 7.4, 7.1, 6.7 or 6.4, or after knockdown of AE2. Cell viability and apoptosis were determined by WST and caspase-3/-7 assays, respectively. Results: Glycochenodeoxycholate (GCDC) uptake in cholangiocytes is pH-dependent. Furthermore, CDC and GCDC (pK_a 4–5) induce cholangiocyte toxicity in a pH-dependent manner: 0.5 mM CDC and 1 mM GCDC at pH 7.4 had no effect on cell viability, but at pH 6.4 decreased viability by >80% and increased caspase activity almost 10- and 30-fold, respectively. Acidification alone had no effect. AE2 knockdown led to 3- and 2-fold enhanced apoptosis induced by 0.75 mM CDC or 2 mM GCDC at pH 7.4. Discussion: These data support our hypothesis of a biliary HCO₃^– umbrella serving to protect human cholangiocytes against bile acid-induced injury. AE2 is a key contributor to this protective mechanism. The development and progression of cholangiopathies, such as primary biliary cirrhosis, may be a consequence of genetic and acquired functional defects of genes involved in maintaining the biliary HCO₃^– umbrella.

show abstract

Section: Introductionmentioning

confidence: 98%

Biliary Bicarbonate Secretion Constitutes a Protective Mechanism against Bile Acid- Induced Injury in Man

Hohenester

Wenniger

Jefferson

et al. 2011

Dig Dis

View full text Add to dashboard Cite

show abstract

“…This regulation is probably indirect activation mediated by cytokine production [5] rather than a direct mechanism as shown with EtOH in gastric mucosa [1,2]. TC is known to cause changes in cell membrane making it more permeable to other extracellular agents [6], increasing apical cell membrane permeability [7], and acting as a detergent eventually disrupting the cell membrane [8]. It further affects the cytoskeleton deteriorating the migratory mechanism of gastric epithelial cells [9].…”

Section: Introductionmentioning

confidence: 99%

Taurocholate Potentiates Ethanol-Induced NF-κB Activation and Inhibits Caspase-3 Activity in Cultured Rat Gastric Mucosal Cells

et al. 2008

View full text Add to dashboard Cite

We have previously shown that ethanol (EtOH) induces protective NF-kappaB activation in gastric surface epithelial cells. This study investigates the defense systems in rat gastric mucosal cells (RGM-1) exposed simultaneously to EtOH and taurocholate (TC) or acetylsalicylic acid (ASA). Simultaneous exposure to ASA and EtOH increased EtOH-induced caspase-3 activity and decreased cell viability, indicating synergetic damaging action. Simultaneous exposure to TC (5 mM) with EtOH (5%) increased EtOH-induced NF-kappaB activation, opposing EtOH-induced decrease in cell membrane integrity and in cell viability as shown by decreasing RelA expression with siRNA technique. Low doses of TC decreased the EtOH (5%) induced caspase-3 activity independently from NF-kappaB pathway and inhibited EtOH-induced decrease in caspase-3 precursor protein levels, also indicating the inhibition of caspase-3 pathway. The TC (5 mM)-induced protection in EtOH exposed tissues seems to have two distinct pathways, inhibition of apoptosis and enhancement of NF-kappaB signaling.

show abstract

“…pH dependency of carrier-independent cell entry and toxicity of bile acids has been established in gastric and esophageal mucosa cells. [12][13][14] Cholangiocyte apoptosis has been shown to drive autoimmunity and inflammation in primary biliary cirrhosis (PBC). 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.…”

mentioning

confidence: 99%

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

Bile acid and bile salt disrupt gastric mucosal barrier in the dog by different mechanisms

Cited by 19 publications

References 0 publications

Biliary Bicarbonate Secretion Constitutes a Protective Mechanism against Bile Acid- Induced Injury in Man

Biliary Bicarbonate Secretion Constitutes a Protective Mechanism against Bile Acid- Induced Injury in Man

Taurocholate Potentiates Ethanol-Induced NF-κB Activation and Inhibits Caspase-3 Activity in Cultured Rat Gastric Mucosal Cells

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

Contact Info

Product

Resources

About

Bile acid and bile salt disrupt gastric mucosal barrier in the dog by different mechanisms

Cited by 19 publications

References 0 publications

Biliary Bicarbonate Secretion Constitutes a Protective Mechanism against Bile Acid- Induced Injury in Man

Biliary Bicarbonate Secretion Constitutes a Protective Mechanism against Bile Acid- Induced Injury in Man

Taurocholate Potentiates Ethanol-Induced NF-κB Activation and Inhibits Caspase-3 Activity in Cultured Rat Gastric Mucosal Cells

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

Contact Info

Product

Resources

About

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