Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, 11751, Egypt.
Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah, 51452, Kingdom of Saudi Arabia.
Naunyn Schmiedebergs Arch Pharmacol. 2020 Oct;393(10):1887-1898. doi: 10.1007/s00210-020-01896-0. Epub 2020 May 20.
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.
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.
Liver toxicity markers, TF, fibrin, cleaved caspase-3, and cyclin D1 as well as histopathology were investigated.
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.
视黄酸受体（RRs），RAR-α 和 RXR-α，作为转录因子发挥作用，调节细胞生长、分化、存活和死亡。肝星状细胞（HSCs）储存视黄酸，并在其激活时将其 RRs 作为脂滴释放。
我们检验了这样一个假设，即在硫代乙酰胺（TAA）诱导的肝损伤过程中，HSCs 中视黄酸受体 RAR-α 和 RXR-α 的丢失依赖于组织因子（TF）。
研究了肝毒性标志物、TF、纤维蛋白、裂解的 caspase-3 和细胞周期蛋白 D1 以及组织病理学。
与 vehicle 处理的小鼠相比，TAA 注射后中央静脉区可见 TF、纤维蛋白、裂解的 caspase-3 和细胞周期蛋白 D1 蛋白表达增加。TAA 诱导的肝损伤可见 RAR-α 和 RXR-α 强烈下调。此外，与正常 vehicle 处理的小鼠相比，TAA 注射后可见肝组织学破坏和中央旁区裂解的 caspase 3 和细胞周期蛋白 D1 的表达。与 TAA 处理的动物相比，TAA/TF 正义（SC）在所有参数中均未见变化。与对照小鼠相比，TAA/TF 反义（AS）处理的小鼠的所有参数和正常组织病理学特征均正常表达。总之，本研究表明，RAR-α 和 RXR-α 的强烈下调可能导致 TAA 诱导的毒性中的肝损伤和特别是 HSCs 的激活。TF-AS 治疗不仅下调 TF 蛋白表达，而且减轻 TAA 诱导的肝毒性中肝 RAR-α 和 RXR-α 的丢失，并抑制激活的凋亡信号。最后，TF 和 RAR-α/RXR-α 是 TAA 诱导的急性肝损伤的重要调节分子。
