Disease relevance of VLDLR

• A soluble VLDLR fragment encompassing the eight complement type repeats and representing the N-terminal part of the receptor was then expressed in the baculovirus system; both the shed protein and the recombinant soluble VLDLR bind minor group viruses and inhibit viral infection of HeLa cells in a concentration-dependent manner [1].
• The regulation of VLDLR expression was studied in JEG-3 and BeWo choriocarcinoma cells, two trophoblast-derived cell lines [2].
• Functional candidate genes in age-related macular degeneration: significant association with VEGF, VLDLR, and LRP6 [3].
• By immunohistochemistry, we demonstrate that VLDLR is mainly expressed by the epithelial cancer cells in these carcinomas [4].
• RESULTS: Immunoreactive VLDLR was abundantly present in human fetal intestinal epithelial and gastric adenocarcinoma cells [5].

Psychiatry related information on VLDLR

• No association detected between very-low-density lipoprotein receptor (VLDL-R) and late-onset Alzheimer's disease in Hong Kong Chinese [6].
• VLDL receptor polymorphism, cognitive impairment, and dementia [7].

High impact information on VLDLR

• We demonstrate that fibroblasts expressing the human VLDL receptor can mediate endocytosis of Lp(a), leading to its degradation within lysosomes [8].
• Presenilin-I, presenilin-II, and VLDL-R associations in early onset Alzheimer's disease [9].
• VLDLR is part of the reelin signaling pathway, which guides neuroblast migration in the cerebral cortex and cerebellum [10].
• The possible roles in AD of the mitochondrial mutation at position 4336, the PS intron 8 polymorphism, and variants in the alpha 1-antichymotrypsin and VLDL-receptor genes, are considered [11].
• Based on an estimated mean binding affinity for the VLDL receptor complex at half saturation of approximately 8.8 X 10(7) liter/mole, it is estimated that 91% of lymphocyte VLDL receptors are occupied at physiologic VLDL concentrations in blood [12].

Chemical compound and disease context of VLDLR

• The VLDLR variant expressed by epithelial cancer cells could function in the clearance of cell-surface-associated serine proteinase/serpin complexes in breast carcinomas [4].

Biological context of VLDLR

• We conclude that 1) VLDLR is expressed in human placental trophoblast cells in a pattern consistent with a role in placental lipid transport; 2) VLDLR expression is high at term relative to that in the first trimester; and 3) the trophoblast VLDLR is subject to down-regulation by cAMP and up-regulation by insulin and fibrate hypolipidemic drugs [2].
• Northern blot analysis of placenta revealed a 2.6-fold increase in VLDLR mRNA at term compared to that in the first trimester [2].
• Incubation of JEG-3 cells with 25-hydroxycholesterol did not lead to sterol negative feedback on VLDLR gene expression, unlike LDLR mRNA, which declined markedly [2].
• Endocytosis was estimated by measuring receptor-associated protein (RAP)-sensitive degradation of radiolabelled complexes by Chinese hamster ovary cells transfected with VLDLR cDNA and by COS-1 cells, which have a high endogenous expression of alpha2MR/LRP [13].
• A Japanese study [Okuizimi, K., et al., Nature Genet., 11 (1995) 207-209] has shown an increased 5 and decreased 8 CGG-repeat allele frequency in the 5' untranslated region of VLDLR in Japanese AD versus normal controls (N) [6].

Anatomical context of VLDLR

• CONCLUSIONS: 1) Abnormal accumulation of LDLR, VLDLR, LRP, and cholesterol within IBM vacuolated muscle fibers suggests novel roles for them in the IBM pathogenesis [14].
• In addition, VLDLR messenger RNA (mRNA) was detected in villous core endothelial cells and cells appearing to be Hofbauer cells [2].
• Immunohistochemical analysis of human placenta with a specific polyclonal antibody detected VLDLR in syncytiotrophoblast and intermediate trophoblast cells [2].
• The LRP seems to be mainly responsible for the hepatic uptake of remnant lipoproteins, while the VLDLR, mainly located in adipose tissue and muscle, might target the lipoproteins to these tissues for fatty acid delivery [15].
• Chinese hamster ovary (CHO) cells transfected with the rabbit VLDL receptor cDNA have now been shown to bind or internalize VLDL (d < 1.006 g/ml) isolated from fasted normolipidemic human subjects with lower affinity than WHHL-VLDL or rabbit beta-VLDL [16].

Associations of VLDLR with chemical compounds

• Insulin (200 mg/L) up-regulated VLDLR message in JEG-3 cells 2-fold, as did the fibrate hypolipidemic drug, clofibric acid [2].
• The high amino acid sequence homology of the VLDLR between two mammalian species suggests that the receptor plays a fundamental role in lipoprotein metabolism and that energy metabolism mediated by triglyceride utilization may be an evolutionarily highly conserved mechanism [17].
• VLDL subfractions were separated and classified as heparin binding (VLDLR, apoE rich) or nonbinding (VLDLNR-1 and VLDLNR-2, both apoE poor) [18].
• With placebo, VLDLR accounted for 41.8% of VLDL in HTG and 49.0% of VLDL in CHLP, reduced to 27.6% and 38.6%, respectively, with gemfibrozil [18].
• Despite the presence of sterol regulatory element-1-like sequences in the VLDL-receptor gene, the transcription of the gene is not down-regulated by sterols [19].

Physical interactions of VLDLR

• These studies confirm that the VLDL receptor binds to and mediates the catabolism of LpL and uPA.PAI-1 complexes [20].
• The VLDL receptor binds lipoproteins that contain apolipoprotein E and consists of five functional domains that resemble the LDL receptor [19].
• However, the VLDL receptor apparently did not show the increase in affinity and decrease in binding of betaVLDL on cooling to 4 degrees C that was exhibited by the LDL receptor [21].
• Binding of urokinase-type plasminogen activator-plasminogen activator inhibitor-1 complex to the endocytosis receptors alpha2-macroglobulin receptor/low-density lipoprotein receptor-related protein and very-low-density lipoprotein receptor involves basic residues in the inhibitor [22].
• Electromobility shift assay was performed to investigate whether the enhanced PAI-1 promoter activity seen in the VLDL receptor overexpressing cells in response to VLDL involved induction of the previously described VLDL-inducible factor(s) binding to the -675 to -653 region of the PAI-1 promoter [23].

Regulatory relationships of VLDLR

• Thus, the VLDL receptor may play a unique role on the vascular endothelium in lipoprotein catabolism by regulating levels of LpL and in the regulation of fibrinolysis by facilitating the removal of urokinase complexed with its inhibitor [20].
• VLDL receptor polymorphism in the control group (p = 0.0403) and LRP exon 3 polymorphism in the CAD group (p = 0.0459) showed significant associations with lipoprotein (a) [Lp(a)] levels [24].
• IFN-gamma inhibited VLDL receptor expression in a dose-and time-dependent manner in macrophages [25].

Other interactions of VLDLR

• 2) Expression of LDLR and VLDLR at normal NMJ suggests physiologic roles for them in transsynaptic signaling pathways, increased internalization of lipoproteins there, or both [14].
• As a receptor for ApoE, very-low-density lipoprotein receptor (VLDLR) might be involved in AD pathogenesis [6].
• These results suggest that CYP17A1 and MTP are susceptibility loci for increased BMD in postmenopausal and premenopausal Japanese women, respectively, and that VLDLR constitutes such a locus in Japanese men [26].
• Infected fibroblasts that express the VLDL receptor mediate the cellular internalization of 125I-labeled LpL and uPA.PAI-1 complexes, leading to their degradation [20].
• CONCLUSIONS: Reductions in Reelin protein and mRNA and Dab 1 mRNA and elevations in Reln receptor VLDLR mRNA demonstrate impairments in the Reelin signaling system in autism, accounting for some of the brain structural and cognitive deficits observed in the disorder [27].

Analytical, diagnostic and therapeutic context of VLDLR

• VLDLR transcripts were also localized in these cells by in situ hybridization histochemistry [2].
• Ligand blotting experiments using RAP and immunoblotting experiments using an anti-VLDL receptor IgG detected the VLDL receptor in detergent extracts of human aortic endothelial cells, human umbilical vein endothelial cells, and human aortic smooth muscle cells [20].
• X-ray crystallography has shown that 60 individual very-low density lipoprotein receptor (VLDLR) modules bind to HRV2 [28].
• The expression of VLDLR subtypes was detected in gastroenteric carcinoma/adjacent normal tissues and three various differentiated human gastric adenocarcinoma cell lines (MKN28, SGC7901 and MKN45) by reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis [29].
• The expression of VLDLR gene could be detected by RT-PCR from the CHO cells transfected with pCD-VR [30].

References