title: Formation of fenestrae in murine liver sinusoids depends on plasmalemma vesicle-associated protein and is required for lipoprotein passage.
abstract: Liver sinusoidal endothelial cells (LSEC) are characterized by the presence of fenestrations that are not bridged by a diaphragm. The molecular mechanisms that control the formation of the fenestrations are largely unclear. Here we report that mice, which are deficient in plasmalemma vesicle-associated protein (PLVAP), develop a distinct phenotype that is caused by the lack of sinusoidal fenestrations. Fenestrations with a diaphragm were not observed in mouse LSEC at three weeks of age, but were present during embryonic life starting from embryonic day 12.5. PLVAP was expressed in LSEC of wild-type mice, but not in that of Plvap-deficient littermates. Plvap(-/-) LSEC showed a pronounced and highly significant reduction in the number of fenestrations, a finding, which was seen both by transmission and scanning electron microscopy. The lack of fenestrations was associated with an impaired passage of macromolecules such as FITC-dextran and quantum dot nanoparticles from the sinusoidal lumen into Disse's space. Plvap-deficient mice suffered from a pronounced hyperlipoproteinemia as evidenced by milky plasma and the presence of lipid granules that occluded kidney and liver capillaries. By NMR spectroscopy of plasma, the nature of hyperlipoproteinemia was identified as massive accumulation of chylomicron remnants. Plasma levels of low density lipoproteins (LDL) were also significantly increased as were those of cholesterol and triglycerides. In contrast, plasma levels of high density lipoproteins (HDL), albumin and total protein were reduced. At around three weeks of life, Plvap-deficient livers developed extensive multivesicular steatosis, steatohepatitis, and fibrosis. PLVAP is critically required for the formation of fenestrations in LSEC. Lack of fenestrations caused by PLVAP deficiency substantially impairs the passage of chylomicron remnants between liver sinusoids and hepatocytes, and finally leads to liver damage.
authors.affiliation: Department of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany.
authors.forename: Leonie
authors.initials: L
authors.lastname: Herrnberger
authors.affiliation: Department of Pharmaceutical Technology, University of Regensburg, Regensburg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Hennig
authors.affiliation: Department of Biophysics and Physical Biochemistry, and Centre of Magnetic Resonance in Chemistry and Biomedicine, University of Regensburg, Regensburg, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Kremer
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Hellerbrand
authors.affiliation: Department of Pharmaceutical Technology, University of Regensburg, Regensburg, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Goepferich
authors.affiliation: Department of Biophysics and Physical Biochemistry, and Centre of Magnetic Resonance in Chemistry and Biomedicine, University of Regensburg, Regensburg, Germany.
authors.forename: Hans Robert
authors.initials: HR
authors.lastname: Kalbitzer
authors.affiliation: Department of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany.
authors.forename: Ernst R
authors.initials: ER
authors.lastname: Tamm
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D053298:Chylomicron Remnants / Q000378:metabolism; D003964:Diaphragm / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006951:Hyperlipoproteinemias / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008099:Liver / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D002352:Carrier Proteins; D053298:Chylomicron Remnants; D008565:Membrane Proteins; C486772:Plvap protein, mouse