Silencing of tissue factor by antisense deoxyoligonucleotide mitigates thioacetamide-induced liver injury
M S Abdel-Bakky1,2, G K Helal3,4, E M El-Sayed3
1Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, 11751, Egypt. M.AbdelBakky@qu.edu.sa.
Background:
Retinoid receptors (RRs), RAR-α and RXR-α, work as transcription factors that regulate cell growth, differentiation, survival, and death. Hepatic stellate cells (HSCs) store retinoid and release its RRs as lipid droplets upon their activation.
Purpose:
We test the hypothesis that loss of retinoid receptors RAR-α and RXR-α from HSCs is dependent on tissue factor (TF) during thioacetamide (TAA)-induced liver injury.
Methods:
Liver toxicity markers, TF, fibrin, cleaved caspase-3, and cyclin D1 as well as histopathology were investigated.
Results:
Increased TF, fibrin, cleaved caspase-3, and cyclin D1 protein expression is seen in zone of central vein after TAA injection compared with vehicle-treated mice. A strong downregulation of RAR-α and RXR-α is seen in TAA-induced liver injury. In addition, histopathological obliteration and pericentral expression of cleaved caspase 3 and cyclin D1 are observed after TAA injection compared with the normal vehicle-treated mice. No changes have been seen in TAA/TF-sense (SC) in whole parameters compared with TAA-treated animals. TAA/TF-antisense (AS)-treated mice show normal expression of all parameters and normal histopathological features when compared with the control mice. In conclusion, this study declares that the strong downregulation of RAR-α and RXR-α may cause liver injury and particularly activation of HSCs in TAA-induced toxicity. TF-AS treatment not only downregulates TF protein expression but also alleviates loss of liver RAR-α and RXR-α and suppresses the activated apoptosis signals in TAA-induced liver toxicity. Finally, TF and RAR-α/RXR-α are important regulatory molecules in TAA induced acute liver injury.
Insights
Loss of retinoid receptors (RAR-α and RXR-α) in hepatic stellate cells contributes to liver injury during thioacetamide-induced toxicity. Tissue factor antisense therapy restored receptor levels and reduced liver damage.
Area of Science:
- Hepatology
- Molecular Biology
- Cellular Biology
Background:
- Retinoid receptors (RAR-α, RXR-α) are transcription factors regulating cell functions.
- Hepatic stellate cells (HSCs) store retinoids and release RRs upon activation.
Purpose of the Study:
- To investigate if the loss of RAR-α and RXR-α from HSCs during thioacetamide (TAA)-induced liver injury is dependent on tissue factor (TF).
Main Methods:
- Assessed liver toxicity markers, TF, fibrin, cleaved caspase-3, and cyclin D1.
- Examined histopathology in TAA-treated mice with and without TF-antisense (AS) treatment.
- Compared results with vehicle-treated and control mice.
Main Results:
- TAA injection increased TF, fibrin, cleaved caspase-3, and cyclin D1, with a strong downregulation of RAR-α and RXR-α.
- TF-AS treatment normalized all investigated parameters and histopathology.
- TF-AS treatment alleviated RAR-α/RXR-α loss and suppressed apoptosis in TAA-induced liver toxicity.
Conclusions:
- Downregulation of RAR-α and RXR-α may cause liver injury and HSC activation in TAA-induced toxicity.
- TF-AS treatment downregulates TF, restores RAR-α/RXR-α, and reduces apoptosis.
- TF and RAR-α/RXR-α are key regulators in TAA-induced acute liver injury.
