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.