TY - JOUR
T1 - Store-operated Ca2+ channels and Stromal Interaction Molecule 1 (STIM1) are targets for the actions of bile acids on liver cells
AU - Aromataris, Edoardo C.
AU - Castro, Joel
AU - Rychkov, Grigori Y.
AU - Barritt, Greg J.
N1 - Funding Information:
We would like to thank Rachael Hughes and Yabin Zhou for preparing isolated rat hepatocytes, Dr T Kurosaki, RIKEN Research Centre for Allergy and Immunology, Kanagwa, Japan, for providing the GFP-STIM1 plasmid, Dr Mike Schell, USUHS, Bethesda for advice on cell transfections, and Dr Alan F Hofmann, University of California, for discussions on bile acid solubility. This work was supported by the Australian Research Council and the National Health and Medical Research Council of Australia and the Flinders Medical Centre Foundation.
PY - 2008/5
Y1 - 2008/5
N2 - Cholestasis is a significant contributor to liver pathology and can lead to primary sclerosis and liver failure. Cholestatic bile acids induce apoptosis and necrosis in hepatocytes but these effects can be partially alleviated by the pharmacological application of choleretic bile acids. These actions of bile acids on hepatocytes require changes in the release of Ca2+ from intracellular stores and in Ca2+ entry. However, the nature of the Ca2+ entry pathway affected is not known. We show here using whole cell patch clamp experiments with H4-IIE liver cells that taurodeoxycholic acid (TDCA) and other choleretic bile acids reversibly activate an inwardly-rectifying current with characteristics similar to those of store-operated Ca2+ channels (SOCs), while lithocholic acid (LCA) and other cholestatic bile acids inhibit SOCs. The activation of Ca2+ entry was observed upon direct addition of the bile acid to the incubation medium, whereas the inhibition of SOCs required a 12 h pre-incubation. In cells loaded with fura-2, choleretic bile acids activated a Gd3+-inhibitable Ca2+ entry, while cholestatic bile acids inhibited the release of Ca2+ from intracellular stores and Ca2+ entry induced by 2,5-di-(tert-butyl)-1,4-benzohydro-quinone (DBHQ). TDCA and LCA each caused a reversible redistribution of stromal interaction molecule 1 (STIM1, the endoplasmic reticulum Ca2+ sensor required for the activation of Ca2+ release-activated Ca2+ channels and some other SOCs) to puncta, similar to that induced by thapsigargin. Knockdown of Stim1 using siRNA caused substantial inhibition of Ca2+-entry activated by choleretic bile acids. It is concluded that choleretic and cholestatic bile acids activate and inhibit, respectively, the previously well-characterised Ca2+-selective hepatocyte SOCs through mechanisms which involve the bile acid-induced redistribution of STIM1.
AB - Cholestasis is a significant contributor to liver pathology and can lead to primary sclerosis and liver failure. Cholestatic bile acids induce apoptosis and necrosis in hepatocytes but these effects can be partially alleviated by the pharmacological application of choleretic bile acids. These actions of bile acids on hepatocytes require changes in the release of Ca2+ from intracellular stores and in Ca2+ entry. However, the nature of the Ca2+ entry pathway affected is not known. We show here using whole cell patch clamp experiments with H4-IIE liver cells that taurodeoxycholic acid (TDCA) and other choleretic bile acids reversibly activate an inwardly-rectifying current with characteristics similar to those of store-operated Ca2+ channels (SOCs), while lithocholic acid (LCA) and other cholestatic bile acids inhibit SOCs. The activation of Ca2+ entry was observed upon direct addition of the bile acid to the incubation medium, whereas the inhibition of SOCs required a 12 h pre-incubation. In cells loaded with fura-2, choleretic bile acids activated a Gd3+-inhibitable Ca2+ entry, while cholestatic bile acids inhibited the release of Ca2+ from intracellular stores and Ca2+ entry induced by 2,5-di-(tert-butyl)-1,4-benzohydro-quinone (DBHQ). TDCA and LCA each caused a reversible redistribution of stromal interaction molecule 1 (STIM1, the endoplasmic reticulum Ca2+ sensor required for the activation of Ca2+ release-activated Ca2+ channels and some other SOCs) to puncta, similar to that induced by thapsigargin. Knockdown of Stim1 using siRNA caused substantial inhibition of Ca2+-entry activated by choleretic bile acids. It is concluded that choleretic and cholestatic bile acids activate and inhibit, respectively, the previously well-characterised Ca2+-selective hepatocyte SOCs through mechanisms which involve the bile acid-induced redistribution of STIM1.
KW - Bile acid
KW - Ca channel
KW - Cholestasis
KW - Liver cell
KW - Patch clamp recording
KW - STIM1
UR - http://www.scopus.com/inward/record.url?scp=41949133562&partnerID=8YFLogxK
U2 - 10.1016/j.bbamcr.2008.02.011
DO - 10.1016/j.bbamcr.2008.02.011
M3 - Article
C2 - 18342630
AN - SCOPUS:41949133562
SN - 0167-4889
VL - 1783
SP - 874
EP - 885
JO - Biochimica et Biophysica Acta - Molecular Cell Research
JF - Biochimica et Biophysica Acta - Molecular Cell Research
IS - 5
ER -