Tauroursodeoxycholic acid protects rat hepatocytes from bile acid–induced apoptosis via activation of survival pathways

Schoemaker, Marieke H.; de la Rosa, Laura Conde; Buist-Homan, Manon; Vrenken, Titia E.; Havinga, Rick; Poelstra, Klaas; Haisma, Hidde J.; Jansen, Peter L. M.; Moshage, Han

doi:10.1002/hep.20246

Cited by 229Drug Transport and Resistance MechanismsAldose Reductase and TaurineLiver physiology and pathology

Tauroursodeoxycholic acid protects rat hepatocytes from bile acid–induced apoptosis via activation of survival pathways

Schoemaker, Marieke H., de la Rosa, Laura Conde, Buist-Homan, Manon, Vrenken, Titia E., Havinga, Rick, Poelstra, Klaas, Haisma, Hidde J., Jansen, Peter L. M. +1 more·2004·Hepatology

DOI 10.1002/hep.20246

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Abstract

Ursodeoxycholic acid (UDCA) is used in the treatment of cholestatic liver diseases, but its mechanism of action is not yet well defined. The aim of this study was to explore the protective mechanisms of the taurine-conjugate of UDCA (tauroursodeoxycholic acid [TUDCA]) against glycochenodeoxycholic acid (GCDCA)-induced apoptosis in primary cultures of rat hepatocytes. Hepatocytes were exposed to GCDCA, TUDCA, the glyco-conjugate of UDCA (GUDCA), and TCDCA. The phosphatidylinositol-3 kinase pathway (PI3K) and nuclear factor-kappaB were inhibited using LY 294002 and adenoviral overexpression of dominant-negative IkappaB, respectively. The role of p38 and extracellular signal-regulated protein kinase mitogen-activated protein kinase (MAPK) pathways were investigated using the inhibitors SB 203580 and U0 126 and Western blot analysis. Transcription was blocked by actinomycin-D. Apoptosis was determined by measuring caspase-3, -9, and -8 activity using fluorimetric enzyme detection, Western blot analysis, immunocytochemistry, and nuclear morphological analysis. Our results demonstrated that uptake of GCDCA is needed for apoptosis induction. TUDCA, but not TCDCA and GUDCA, rapidly inhibited, but did not delay, apoptosis at all time points tested. However, the protective effect of TUDCA was independent of its inhibition of caspase-8. Up to 6 hours of preincubation with TUDCA before addition of GCDCA clearly decreased GCDCA-induced apoptosis. At up to 1.5 hours after exposure with GCDCA, the addition of TUDCA was still protective. This protection was dependent on activation of p38, ERK MAPK, and PI3K pathways, but independent of competition on the cell membrane, NF-kappaB activation, and transcription. In conclusion, TUDCA contributes to the protection against GCDCA-induced mitochondria-controlled apoptosis by activating survival pathways.

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Authors: Schoemaker, M. H., de la Rosa, L. C., Buist-Homan, M., Vrenken, T. E., Havinga, R., Poelstra, K., Haisma, H. J., Jansen, P. L. M., & Moshage, H.
Affiliations: University of Groningen (NL)
Corresponding author: Moshage, Han
ORCID: Schoemaker, Marieke H.
Poelstra, Klaas
Haisma, Hidde J.
Moshage, Han
Venue: Hepatology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2004-06
Volume: 39
Issue: 6
Pages: 1563-1573
ISSN: 0270-9139 (ISSN-L)
DOI: 10.1002/hep.20246
OpenAlex: W2041827858
Cited by: 229
References: 42
Citations by year: 2026: 4 · 2025: 9 · 2024: 3 · 2023: 6 · 2022: 5 · 2021: 13 · 2020: 14 · 2019: 11 · 2018: 5 · 2017: 13 · 2016: 13 · 2015: 11 · 2014: 9 · 2013: 10 · 2012: 11
FWCI: 6.71
Type: journal article
Language: en
Open access: closed
Licence: doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 4109 d)
Locations: Hepatology (publishedVersion)
PubMed (publishedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
Pure Amsterdam UMC (submittedVersion)
University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
Topics: Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords: tauroursodeoxycholic acid, ursodeoxycholic acid, hepatoprotection, glycochenodeoxycholic acid, p38 MAPK, ERK MAPK, PI3K signaling, NF-κB, caspase-8, caspase-3, caspase-9, cholestatic liver disease, bile acid absorption
MeSH terms: Animals, Bile Acids and Salts, Carrier Proteins, Cell Membrane, Cell Survival, Glycochenodeoxycholic Acid, Male, Mitochondria, Taurochenodeoxycholic Acid, Rats, Wistar, Apoptosis, Caspases, Mitogen-Activated Protein Kinases, Hepatocytes, Membrane Transport Proteins, Symporters, Organic Anion Transporters, Sodium-Dependent, p38 Mitogen-Activated Protein Kinases, Rats, Caspase 3, Caspase 9, Caspase Inhibitors

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Tauroursodeoxycholic acid protects rat hepatocytes from bile acid–induced apoptosis via activation of survival pathways

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