Bile acids inhibit Na+/H+ exchanger and Cl/HCO3 exchanger activities via cellular energy breakdown and Ca2+ overload in human colonic crypts

Pallagi-Kunstár, K. Farkas, J. Maléth, Z. Rakonczay, F. Nagy, T. Molnár, Z. Szepes, V. Venglovecz, J. Lonovics, Z. Rázga, T. Wittmann, P. Hegyi

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7 Citations (Scopus)

Abstract

Bile acids play important physiological role in the solubilisation and absorption of dietary lipids. However, under pathophysiological conditions, such as short bowel syndrome, they can reach the colon in high concentrations inducing diarrhoea. In this study, our aim was to characterise the cellular pathomechanism of bile-induced diarrhoea using human samples. Colonic crypts were isolated from biopsies of patients (controls with negative colonoscopic findings) and of cholecystectomised/ileum-resected patients with or without diarrhoea. In vitro measurement of the transporter activities revealed impaired Na+/H+ exchanger (NHE) and Cl/HCO3 exchanger (CBE) activities in cholecystectomised/ileum-resected patients suffering from diarrhoea, compared to control patients. Acute treatment of colonic crypts with 0.3 mM chenodeoxycholate caused dose-dependent intracellular acidosis; moreover, the activities of acid/base transporters (NHE and CBE) were strongly impaired. This concentration of chenodeoxycholate did not cause morphological changes in colonic epithelial cells, although significantly reduced the intracellular ATP level, decreased mitochondrial transmembrane potential and caused sustained intracellular Ca2+ elevation. We also showed that chenodeoxycholate induced Ca2+ release from the endoplasmic reticulum and extracellular Ca2+ influx contributing to the Ca2+ elevation. Importantly, our results suggest that the chenodeoxycholate-induced inhibition of NHE activities was ATP-dependent, whereas the inhibition of CBE activity was mediated by the sustained Ca2+ elevation. We suggest that bile acids inhibit the function of ion transporters via cellular energy breakdown and Ca2+ overload in human colonic epithelial cells, which can reduce fluid and electrolyte absorption in the colon and promote the development of diarrhoea.

Original languageEnglish
Article number11
Pages (from-to)1277-1290
Number of pages14
JournalPflugers Archiv European Journal of Physiology
Volume467
Issue number6
DOIs
Publication statusPublished - Jul 13 2014

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Chloride-Bicarbonate Antiporters
Chenodeoxycholic Acid
Sodium-Hydrogen Antiporter
Chemical beam epitaxy
Bile Acids and Salts
Diarrhea
Ileum
Adenosine Triphosphate
Colon
Epithelial Cells
Biopsy
Short Bowel Syndrome
Electrolytes
Acidosis
Bile
Endoplasmic Reticulum
Membrane Potentials
Ions
Lipids
Acids

Keywords

  • Bile acids
  • Colonic epithelial cells
  • Intracellular Ca<sup>2+</sup>
  • Ion transporters

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Physiology (medical)

Cite this

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title = "Bile acids inhibit Na+/H+ exchanger and Cl−/HCO3 − exchanger activities via cellular energy breakdown and Ca2+ overload in human colonic crypts",
abstract = "Bile acids play important physiological role in the solubilisation and absorption of dietary lipids. However, under pathophysiological conditions, such as short bowel syndrome, they can reach the colon in high concentrations inducing diarrhoea. In this study, our aim was to characterise the cellular pathomechanism of bile-induced diarrhoea using human samples. Colonic crypts were isolated from biopsies of patients (controls with negative colonoscopic findings) and of cholecystectomised/ileum-resected patients with or without diarrhoea. In vitro measurement of the transporter activities revealed impaired Na+/H+ exchanger (NHE) and Cl−/HCO3 − exchanger (CBE) activities in cholecystectomised/ileum-resected patients suffering from diarrhoea, compared to control patients. Acute treatment of colonic crypts with 0.3 mM chenodeoxycholate caused dose-dependent intracellular acidosis; moreover, the activities of acid/base transporters (NHE and CBE) were strongly impaired. This concentration of chenodeoxycholate did not cause morphological changes in colonic epithelial cells, although significantly reduced the intracellular ATP level, decreased mitochondrial transmembrane potential and caused sustained intracellular Ca2+ elevation. We also showed that chenodeoxycholate induced Ca2+ release from the endoplasmic reticulum and extracellular Ca2+ influx contributing to the Ca2+ elevation. Importantly, our results suggest that the chenodeoxycholate-induced inhibition of NHE activities was ATP-dependent, whereas the inhibition of CBE activity was mediated by the sustained Ca2+ elevation. We suggest that bile acids inhibit the function of ion transporters via cellular energy breakdown and Ca2+ overload in human colonic epithelial cells, which can reduce fluid and electrolyte absorption in the colon and promote the development of diarrhoea.",
keywords = "Bile acids, Colonic epithelial cells, Intracellular Ca<sup>2+</sup>, Ion transporters",
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T1 - Bile acids inhibit Na+/H+ exchanger and Cl−/HCO3 − exchanger activities via cellular energy breakdown and Ca2+ overload in human colonic crypts

AU - Pallagi-Kunstár,

AU - Farkas, K.

AU - Maléth, J.

AU - Rakonczay, Z.

AU - Nagy, F.

AU - Molnár, T.

AU - Szepes, Z.

AU - Venglovecz, V.

AU - Lonovics, J.

AU - Rázga, Z.

AU - Wittmann, T.

AU - Hegyi, P.

PY - 2014/7/13

Y1 - 2014/7/13

N2 - Bile acids play important physiological role in the solubilisation and absorption of dietary lipids. However, under pathophysiological conditions, such as short bowel syndrome, they can reach the colon in high concentrations inducing diarrhoea. In this study, our aim was to characterise the cellular pathomechanism of bile-induced diarrhoea using human samples. Colonic crypts were isolated from biopsies of patients (controls with negative colonoscopic findings) and of cholecystectomised/ileum-resected patients with or without diarrhoea. In vitro measurement of the transporter activities revealed impaired Na+/H+ exchanger (NHE) and Cl−/HCO3 − exchanger (CBE) activities in cholecystectomised/ileum-resected patients suffering from diarrhoea, compared to control patients. Acute treatment of colonic crypts with 0.3 mM chenodeoxycholate caused dose-dependent intracellular acidosis; moreover, the activities of acid/base transporters (NHE and CBE) were strongly impaired. This concentration of chenodeoxycholate did not cause morphological changes in colonic epithelial cells, although significantly reduced the intracellular ATP level, decreased mitochondrial transmembrane potential and caused sustained intracellular Ca2+ elevation. We also showed that chenodeoxycholate induced Ca2+ release from the endoplasmic reticulum and extracellular Ca2+ influx contributing to the Ca2+ elevation. Importantly, our results suggest that the chenodeoxycholate-induced inhibition of NHE activities was ATP-dependent, whereas the inhibition of CBE activity was mediated by the sustained Ca2+ elevation. We suggest that bile acids inhibit the function of ion transporters via cellular energy breakdown and Ca2+ overload in human colonic epithelial cells, which can reduce fluid and electrolyte absorption in the colon and promote the development of diarrhoea.

AB - Bile acids play important physiological role in the solubilisation and absorption of dietary lipids. However, under pathophysiological conditions, such as short bowel syndrome, they can reach the colon in high concentrations inducing diarrhoea. In this study, our aim was to characterise the cellular pathomechanism of bile-induced diarrhoea using human samples. Colonic crypts were isolated from biopsies of patients (controls with negative colonoscopic findings) and of cholecystectomised/ileum-resected patients with or without diarrhoea. In vitro measurement of the transporter activities revealed impaired Na+/H+ exchanger (NHE) and Cl−/HCO3 − exchanger (CBE) activities in cholecystectomised/ileum-resected patients suffering from diarrhoea, compared to control patients. Acute treatment of colonic crypts with 0.3 mM chenodeoxycholate caused dose-dependent intracellular acidosis; moreover, the activities of acid/base transporters (NHE and CBE) were strongly impaired. This concentration of chenodeoxycholate did not cause morphological changes in colonic epithelial cells, although significantly reduced the intracellular ATP level, decreased mitochondrial transmembrane potential and caused sustained intracellular Ca2+ elevation. We also showed that chenodeoxycholate induced Ca2+ release from the endoplasmic reticulum and extracellular Ca2+ influx contributing to the Ca2+ elevation. Importantly, our results suggest that the chenodeoxycholate-induced inhibition of NHE activities was ATP-dependent, whereas the inhibition of CBE activity was mediated by the sustained Ca2+ elevation. We suggest that bile acids inhibit the function of ion transporters via cellular energy breakdown and Ca2+ overload in human colonic epithelial cells, which can reduce fluid and electrolyte absorption in the colon and promote the development of diarrhoea.

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KW - Colonic epithelial cells

KW - Intracellular Ca<sup>2+</sup>

KW - Ion transporters

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