Tissue factor dependent liver injury causes release of retinoid receptors (RXR-α and RAR-α) as lipid droplets
Tissue factor dependent liver injury causes release of retinoid receptors (RXR-α and RAR-α) as lipid droplets
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DOI：
10.1016/j.bbrc.2011.05.127
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发表时间：
2011-06-24
影响因子：
3.1
通讯作者：
Ashfaq, Mohammad K.
中科院分区：
文献类型：
--
作者：
Abdel-Bakky, Mohamed Sadek;Hammad, Mohamed A.;Ashfaq, Mohammad K.
肝星状细胞（HSC）储存类维生素A，并在激活后分化为肌成纤维细胞样细胞，在此过程中它们失去含有类维生素A的脂滴。我们先前报道了MCT/LPS肝毒性模型中组织因子（TF）的激活。我们现在报告TF参与释放维甲酸受体RAR-α和RXR-α作为累积的脂滴在野百合碱/脂多糖（MCT/LPS）-肝损伤。RAR-α在肝星状细胞、胆管和门静脉内皮细胞中观察到组成性表达，而RXR-α在某些中央周围肝细胞和肝星状细胞中观察到表达。给予亚毒性剂量的MCT或LPS强烈增加HSC和肝细胞中TF和RXR-α的表达，但不增加RAR-α的表达。然而，MCT/LPS共处理显示在坏死区域附近存在含有RAR-α和RXR-α的不溶性液滴。用TF反义寡核苷酸（TF-AS ODN）阻断TF可导致正常肝细胞中RXR-α的表达，并上调HSC中RAR-α的表达。该研究显示了在肝损伤中RAR-α和RXR-α作为不溶性脂滴在体内释放的明确证据。这些不溶性的RAR-α和RXR-α液滴可能被用作一般肝损伤和特别是HSC活化的标志物。RXR-α似乎比RAR-α更敏感，因为它甚至受到亚毒性剂量的MCT或LPS的影响。IF-AS处理不仅下调TF，而且消除了肝细胞中RAR-α和RXR-α作为不溶性脂滴的释放，这一事实表明TF是RAR-α和RXR-α的重要调节分子。(C)2011 Elsevier Inc. All rights reserved.
Hepatic stellate cells (HSC) store retinoids and upon activation differentiate into myofibroblast-like cells, a process whereby they lose their retinoid-containing lipid droplets. We reported earlier, activation of tissue factor (TF) in our MCT/LPS hepatotoxicity model. We now report the involvement of TF in the release of retinoid receptors RAR-alpha and RXR-alpha as accumulated lipid droplet during monocrotaline/lipopolysaccharide (MCT/LPS)-liver injury. Constitutive expression of RAR-alpha was observed in HSCs and endothelial cells of bile duct and portal vein, while expression of RXR-alpha was observed in certain pericentral hepatocytes and HSCs. Administration of sub-toxic doses of MCT or LPS strongly increased TF and RXR-alpha but not RAR-alpha expressions in HSCs and hepatocytes. However MCT/LPS co-treatment showed insoluble droplets containing RAR-alpha and RXR-alpha in the vicinity of the necrotic areas. Blocking TF with TF antisense oligonucleotides (TF-AS ODN) led to normal hepatocyte expression of RXR-alpha and upregulated the expression of RAR-alpha in HSCs. This study shows clear evidence of in vivo release of RAR-alpha and RXR-alpha as insoluble lipid droplets in liver injury. It is possible that these insoluble droplets of RAR-alpha and RXR-alpha could be used as markers for liver injury in general and activation of HSCs in particular. RXR-alpha appears to be a more sensitive than RAR-alpha as it was affected by even the subtoxic doses of MCT or LPS. The fact that IF-AS treatment not only down-regulated TF but also obliterated the release of RAR-alpha and RXR-alpha as insoluble lipid droplets in hepatocytes points towards TF being an important regulatory molecule for RAR-alpha and RXR-alpha. (C) 2011 Elsevier Inc. All rights reserved.