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  3. Medizin - Open Access LMU - Teil 17/22 Podcast
  4. Biliary Bicarbonate Secretion Constitutes a Protective Mechanism against Bile Acid-Induced Injury in Man
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 HCO(3)(-) 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 HCO(3)(-) 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 HCO(3)(-) umbrella. Copyright
(C) 2011 S. Karger AG, Basel

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

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