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The bile acid glycochenodeoxycholate induces trail-receptor 2/DR5 expression and apoptosis
H Higuchi1, S F Bronk, Y Takikawa
1Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic, and Foundation, Rochester, Minnesota 55905, USA.
The Journal of Biological Chemistry
|August 17, 2001
Summary
Toxic bile salts trigger hepatocyte apoptosis via Fas-independent pathways. Glycochenodeoxycholate (GCDC) upregulates TRAIL-R2/DR5, inducing cell death, offering new insights into liver injury mechanisms.
Area of Science:
- Hepatology
- Cell Biology
- Molecular Toxicology
Background:
- Toxic bile acids induce hepatocyte apoptosis through both Fas-dependent and -independent pathways.
- Understanding the precise mechanisms of Fas-independent apoptosis is crucial for liver disease research.
Purpose of the Study:
- To investigate the cellular mechanisms underlying Fas-independent, bile acid-mediated hepatocyte apoptosis.
- To elucidate the role of death receptors in bile acid-induced liver cell death.
Main Methods:
- HuH-7 cells, deficient in Fas, were transfected with a bile acid transporter.
- Cells were treated with glycochenodeoxycholate (GCDC) and analyzed for apoptosis, cytochrome c release, and death receptor expression.
- Techniques included dominant-negative FADD transfection, CrmA transfection, caspase 8 inhibition, and RT-PCR.
Main Results:
- GCDC induced time- and concentration-dependent apoptosis and mitochondrial cytochrome c release in HuH-7 cells.
- Apoptosis was inhibited by blocking FADD, CrmA, or caspase 8, indicating death receptor involvement.
- GCDC treatment significantly increased TRAIL-R2/DR5 mRNA and protein expression, leading to receptor aggregation.
Conclusions:
- Fas-independent hepatocyte apoptosis induced by bile acids is mediated through death receptors, specifically TRAIL-R2/DR5.
- Bile acids regulate TRAIL-R2/DR5 expression, providing novel insights into mechanisms of hepatocyte apoptosis and liver injury.