title: Expression of the megalin C-terminal fragment by macrophages during liver fibrogenesis in mice.
abstract: The low-density-lipoprotein receptor megalin (LRP2, gp330) is strongly expressed in the kidney, where it is responsible for the resorption of metabolites from primary urine. One of the main ligands is the complex of retinol and retinol binding protein. Megalin has been hypothesized to be part of the retinol storage system in liver. Considering the role of hepatic stellate cells in retinol storage and fibrogenesis we investigated mouse strains that developed different degrees of fibrosis after challenge with CCl(4). Immunoblotting revealed the invariable expression of the megalin C-terminal fragment independent of liver damage in all strains. However, only a specific cell population in centrilobular areas of fibrotic livers from DBA/2J mice, which were most susceptible for CCl(4)-induced fibrogenesis in our study, was stained using megalin-specific antibodies. Double immunostaining indicated that a subset of hepatic macrophages might represent the megalin-expressing cells in fibrotic liver. Fluorescence activated cell sorting based isolation of hepatic macrophages and megalin specific expression analysis demonstrated the transcription of the whole megalin gene in liver macrophages. We argue that megalin might exhibit a proinflammatory effect by the uptake of retinoids in recruited monocytes, which thereby differentiate to liver macrophages and potentiate fibrogenesis by the release of proinflammatory mediators. Otherwise, megalin might be activated in macrophages during advanced fibrogenesis and act as a negative regulator of proinflammatory genes.
authors.affiliation: Department of Internal Medicine I, University Hospital Bonn, Germany. ursula.pieper-fuerst@ukb.uni-bonn.de
authors.forename: Ursula
authors.initials: U
authors.lastname: Pieper-Fürst
authors.forename: Rabea
authors.initials: R
authors.lastname: Hall
authors.forename: Sebastian
authors.initials: S
authors.lastname: Huss
authors.forename: Katrin
authors.initials: K
authors.lastname: Hochrath
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Fischer
authors.forename: Frank
authors.initials: F
authors.lastname: Tacke
authors.forename: Ralf
authors.initials: R
authors.lastname: Weiskirchen
authors.forename: Frank
authors.initials: F
authors.lastname: Lammert
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D002251:Carbon Tetrachloride; D003001:Cloning, Molecular; D005434:Flow Cytometry; D006909:Hydroxyproline / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011817:Rabbits; D060888:Real-Time Polymerase Chain Reaction; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D026561:Low Density Lipoprotein Receptor-Related Protein-2; C055127:Lrp2 protein, mouse; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D002251:Carbon Tetrachloride; D000410:Alanine Transaminase; D006909:Hydroxyproline