title: Tissue factor dependent liver injury causes release of retinoid receptors (RXR-α and RAR-α) as lipid droplets.
abstract: 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.
authors.affiliation: National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS 38677, USA. mkashfaq@olemiss.edu
authors.forename: Mohamed Sadek
authors.initials: MS
authors.lastname: Abdel-Bakky
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Hammad
authors.forename: Larry A
authors.initials: LA
authors.lastname: Walker
authors.forename: Mohammad K
authors.initials: MK
authors.lastname: Ashfaq
mesh_terms: D000818:Animals; D050356:Lipid Metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008815:Mice, Inbred Strains; D016686:Monocrotaline / Q000633:toxicity; D016376:Oligonucleotides, Antisense; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D047490:Retinoid X Receptor alpha / Q000378:metabolism*; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D016376:Oligonucleotides, Antisense; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047490:Retinoid X Receptor alpha; D016686:Monocrotaline; D013925:Thromboplastin