National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
Biochem Biophys Res Commun. 2011 Jun 24;410(1):146-51. doi: 10.1016/j.bbrc.2011.05.127. Epub 2011 May 30.
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-α and RXR-α as accumulated lipid droplet during monocrotaline/lipopolysaccharide (MCT/LPS)-liver injury. Constitutive expression of RAR-α was observed in HSCs and endothelial cells of bile duct and portal vein, while expression of RXR-α was observed in certain pericentral hepatocytes and HSCs. Administration of sub-toxic doses of MCT or LPS strongly increased TF and RXR-α but not RAR-α expressions in HSCs and hepatocytes. However MCT/LPS co-treatment showed insoluble droplets containing RAR-α and RXR-α in the vicinity of the necrotic areas. Blocking TF with TF antisense oligonucleotides (TF-AS ODN) led to normal hepatocyte expression of RXR-α and upregulated the expression of RAR-α in HSCs. This study shows clear evidence of in vivo release of RAR-α and RXR-α as insoluble lipid droplets in liver injury. It is possible that these insoluble droplets of RAR-α and RXR-α could be used as markers for liver injury in general and activation of HSCs in particular. RXR-α appears to be a more sensitive than RAR-α as it was affected by even the subtoxic doses of MCT or LPS. The fact that TF-AS treatment not only down-regulated TF but also obliterated the release of RAR-α and RXR-α as insoluble lipid droplets in hepatocytes points towards TF being an important regulatory molecule for RAR-α and RXR-α.
肝星状细胞（HSC）储存类视黄醇，激活后分化为肌成纤维细胞样细胞，在此过程中，它们失去了含有类视黄醇的脂滴。我们之前报道过，在我们的 MCT/LPS 肝毒性模型中，组织因子（TF）的激活。我们现在报告 TF 参与了视黄醇受体 RAR-α 和 RXR-α的释放，这些受体在单环毛蚓/脂多糖（MCT/LPS）-肝损伤期间作为累积的脂滴。RAR-α 在 HSC 和胆管及门静脉的内皮细胞中呈组成性表达，而 RXR-α 在某些中央区肝细胞和 HSC 中表达。给予亚毒性剂量的 MCT 或 LPS 可强烈增加 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 联合处理显示在坏死区域附近有不溶性含有 RAR-α和 RXR-α的脂滴。用 TF 反义寡核苷酸（TF-AS ODN）阻断 TF 导致 RXR-α在肝细胞中的正常表达，并上调 HSC 中 RAR-α的表达。这项研究清楚地证明了 RAR-α和 RXR-α作为不溶性脂滴在肝损伤中的体内释放。这些不溶性 RAR-α和 RXR-α 可能可作为一般肝损伤和 HSC 激活的标志物。RXR-α似乎比 RAR-α更敏感，因为即使是亚毒性剂量的 MCT 或 LPS 也会影响它。TF-AS 治疗不仅下调了 TF，而且消除了肝细胞中不溶性 RAR-α和 RXR-α作为脂滴的释放，这表明 TF 是 RAR-α和 RXR-α的重要调节分子。
