title: Lipid emulsions potently increase transgene expression in hepatocytes after adenoviral transfer.
abstract: Elimination of Kupffer cells by cytotoxic clodronate liposomes increases transgene expression in the liver after adenoviral transfer. Here, we demonstrate that empty l-alpha-phosphatidylcholine liposomes block uptake of vectors in the reticuloendothelial cells of the liver and increase human apolipoprotein (apo) A-I (approved gene symbol apo A-I) expression in C57BL/6 (1.3-fold) and Balb/c mice (3.1-fold) to the same extent as clodronate liposomes (1.5- and 3.4-fold, respectively). A similar elevation of human apo A-I levels was induced by the lipid emulsion Intralipid (1.5- and 2.8-fold in C57BL/6 and Balb/c mice, respectively). Not only Kupffer cells but also hepatic sinusoidal endothelial cells (HSEC) constitute the reticuloendothelial cells of the liver. The uptake of adenoviral vectors 1 h after transfer in C57BL/6 mice was 2.9-fold lower in Kupffer cells than in HSEC. In contrast, Kupffer cell uptake in Balb/c mice was 2.6-fold higher than in HSEC. Vector uptake in reticuloendothelial cells of the liver was reduced and transgene expression was increased in splenectomized and Rag2-deficient Balb/c mice but not in splenectomized and Rag1-deficient C57BL/6 mice. In conclusion, lipid emulsions for parenteral clinical use block uptake of adenoviral vectors by the reticuloendothelial cells of the liver and potently increase transgene expression.
authors.affiliation: Center for Molecular and Vascular Biology, University of Leuven, Campus Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Snoeys
authors.forename: Geertrui
authors.initials: G
authors.lastname: Mertens
authors.forename: Joke
authors.initials: J
authors.lastname: Lievens
authors.forename: Theo
authors.initials: T
authors.lastname: van Berkel
authors.forename: Désiré
authors.initials: D
authors.lastname: Collen
authors.forename: Erik A L
authors.initials: EA
authors.lastname: Biessen
authors.forename: Bart
authors.initials: B
authors.lastname: De Geest
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D016632:Apolipoprotein A-I / Q000096:biosynthesis* / Q000235:genetics; D004002:Clodronic Acid / Q000737:chemistry / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005217:Fat Emulsions, Intravenous / Q000737:chemistry / Q000494:pharmacology*; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D022781:Hepatocytes / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008081:Liposomes; D008099:Liver / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010713:Phosphatidylcholines / Q000737:chemistry / Q000494:pharmacology*; D013156:Splenectomy; D014161:Transduction, Genetic; D019076:Transgenes
chemical_list: D016632:Apolipoprotein A-I; D004268:DNA-Binding Proteins; D005217:Fat Emulsions, Intravenous; D018398:Homeodomain Proteins; D008081:Liposomes; D010713:Phosphatidylcholines; C499308:Rag2 protein, mouse; D004002:Clodronic Acid; C064658:RAG-1 protein