The Bile Acid Glycochenodeoxycholate Induces TRAIL-Receptor 2/DR5 Expression and Apoptosis

Hajime Higuchi, Steven F. Bronk, Yasuhiro Takikawa, Nathan Werneburg, Rishu Takimoto, Wafik El-Deiry, Gregory James Gores

Research output: Contribution to journalArticle

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Abstract

Toxic bile salts induce hepatocyte apoptosis by both Fas-dependent and -independent mechanisms. In this study, we examined the cellular mechanisms responsible for Fas-independent, bile acid-mediated apoptosis. HuH-7 cells, which are known to be Fas deficient, were stably transfected with the sodium-dependent bile acid transporting polypeptide. The toxic bile acid glycochenodeoxycholate (GCDC)-induced apoptosis in these cells in a time- and concentration-dependent manner. Apoptosis and mitochondrial cytochrome c release were inhibited by transfection with dominant negative FADD, CrmA transfection, or treatment with the selective caspase 8 inhibitor IETD-CHO. These observations suggested the Fas-independent apoptosis was also death receptor mediated. Reverse transcriptase-polymerase chain reaction demonstrated tumor necrosis factor-R1, tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-R1/DR4, -R2/DR5, and TRAIL, but not tumor necrosis fator-α expression by these cells. GCDC treatment increased expression of TRAIL-R2/DR5 mRNA and protein 10-fold while expression of TRAIL-R1 was unchanged. Furthermore, aggregation of TRAIL-R2/DR5, but not TRAIL-R1/DR4 was observed following GCDC treatment of the cells. Induction of TRAIL-R2/DR5 expression and apoptosis by bile acids provides new insights into the mechanisms of hepatocyte apoptosis and the regulation of TRAIL-R2/DR5 expression.

Original languageEnglish (US)
Pages (from-to)38610-38618
Number of pages9
JournalJournal of Biological Chemistry
Volume276
Issue number42
DOIs
StatePublished - Oct 19 2001

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Glycochenodeoxycholic Acid
TNF-Related Apoptosis-Inducing Ligand Receptors
Bile Acids and Salts
Apoptosis
Poisons
Transfection
Hepatocytes
Tumor Necrosis Factor-alpha
Death Domain Receptors
Caspase Inhibitors
Caspase 8
Polymerase chain reaction
RNA-Directed DNA Polymerase
Cytochromes c
Reverse Transcriptase Polymerase Chain Reaction
Tumors
Necrosis
Agglomeration
Sodium
Cells

ASJC Scopus subject areas

  • Biochemistry

Cite this

Higuchi, H., Bronk, S. F., Takikawa, Y., Werneburg, N., Takimoto, R., El-Deiry, W., & Gores, G. J. (2001). The Bile Acid Glycochenodeoxycholate Induces TRAIL-Receptor 2/DR5 Expression and Apoptosis. Journal of Biological Chemistry, 276(42), 38610-38618. https://doi.org/10.1074/jbc.M105300200

The Bile Acid Glycochenodeoxycholate Induces TRAIL-Receptor 2/DR5 Expression and Apoptosis. / Higuchi, Hajime; Bronk, Steven F.; Takikawa, Yasuhiro; Werneburg, Nathan; Takimoto, Rishu; El-Deiry, Wafik; Gores, Gregory James.

In: Journal of Biological Chemistry, Vol. 276, No. 42, 19.10.2001, p. 38610-38618.

Research output: Contribution to journalArticle

Higuchi, H, Bronk, SF, Takikawa, Y, Werneburg, N, Takimoto, R, El-Deiry, W & Gores, GJ 2001, 'The Bile Acid Glycochenodeoxycholate Induces TRAIL-Receptor 2/DR5 Expression and Apoptosis', Journal of Biological Chemistry, vol. 276, no. 42, pp. 38610-38618. https://doi.org/10.1074/jbc.M105300200
Higuchi H, Bronk SF, Takikawa Y, Werneburg N, Takimoto R, El-Deiry W et al. The Bile Acid Glycochenodeoxycholate Induces TRAIL-Receptor 2/DR5 Expression and Apoptosis. Journal of Biological Chemistry. 2001 Oct 19;276(42):38610-38618. https://doi.org/10.1074/jbc.M105300200
Higuchi, Hajime ; Bronk, Steven F. ; Takikawa, Yasuhiro ; Werneburg, Nathan ; Takimoto, Rishu ; El-Deiry, Wafik ; Gores, Gregory James. / The Bile Acid Glycochenodeoxycholate Induces TRAIL-Receptor 2/DR5 Expression and Apoptosis. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 42. pp. 38610-38618.
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