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.
Highlights
Endothelial cells of liver sinusoids differ from that of other capillaries because of the presence of open fenestrations and the absence of a basal lamina [1,2,3,4]
The reduced permeability impairs the passage of chylomicron remnants and other lipoproteins such as low density lipoproteins (LDL) between the lumen of liver sinusoids and hepatocytes, a scenario that causes hyperlipoproteinemia and results in liver injury
Our data that show the expression of mRNA for Plvap in the mouse liver, albeit at levels that are lower than in organs harboring capillaries with abundant endothelial diaphragms, are essentially comparable to findings of others, which detected Plvap mRNA in rat, mouse or human liver [13, 15, 30]
Summary
Endothelial cells of liver sinusoids differ from that of other capillaries because of the presence of open fenestrations and the absence of a basal lamina [1,2,3,4]. A specific function of liver sinusoids is the filtration of particles that are exchanged between the sinusoidal lumen and the space of Disse, allowing only particles smaller than the fenestrae to reach the hepatocytes or to leave the space of Disse [7]. Such a filter function appears to be especially important for the passage of lipoproteins. In support of this are observations of numerous chylomicron remnants with a size smaller than the diameter of fenestrations in the space of Disse of breastfeeded rat pups [8]. Others did not find evidence supporting the assumption that the diameter of liver sinusoidal fenestrae is a major determinant of plasma lipoprotein levels [10]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
