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Gene Review

Vldlr  -  very low density lipoprotein receptor

Mus musculus

Synonyms: AA408956, AI451093, AW047288, VLDL receptor, VLDL-R, ...
 
 

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Disease relevance of Vldlr

  • Further testing of the use of the VLDLR gene as a therapeutic gene for the treatment of hypercholesterolemia is warranted [1].
  • We generated a replication-defective adenovirus (AdmVLDLR) containing mouse VLDLR cDNA driven by a cytomegalovirus promoter [1].
  • Transduction of cultured Hepa (mouse hepatoma) cells and LDLR-deficient CHO-ldlA7 cells in vitro by the virus led to high-level expression of immunoreactive VLDLR proteins with molecular sizes of 143 kDa and 161 kDa [1].
  • Infusion of recombinant adenoviruses containing the VLDL receptor gene corrected the dsylipidaemia in the FH mouse and circumvented immune responses to the transgene leading to a more prolonged metabolic correction [2].
  • However, little is known about the function and regulation of the VLDL-R during sepsis [3].
 

High impact information on Vldlr

  • Reelin promotes hippocampal dendrite development through the VLDLR/ApoER2-Dab1 pathway [4].
  • Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation [5].
  • Taken together, these findings suggest that Reelin acts via VLDLR and ApoER2 to regulate Disabled-1 tyrosine phosphorylation and microtubule function in neurons [5].
  • We also demonstrate the expression of the VLDL receptor in macrophages present in human atherosclerotic lesions [6].
  • LRP-1-deficient MEFs demonstrated increased Rac1 activation compared with LRP-1-expressing MEFs, and this property was reversed by expressing the VLDL receptor, a member of the same gene family as LRP-1, with overlapping ligand-binding specificity [7].
  • VLDLR is a potent endogenous inhibitor negatively regulating angiogenic properties of retinal vascular endothelial cells (RVECs). Loss of VLDLR activates RVECs and significantly enhances angiogenesis in vivo and in vitro [8].
 

Chemical compound and disease context of Vldlr

  • These observations were supported by a strong decrease in average adipocyte size in VLDLR-/- mice of both obesity models, implying reduced adipocyte triglyceride storage in the absence of the VLDLR [9].
  • The vldlr–/– mouse exhibits histologic and angiographic characteristics of retinal angiomatous proliferation (RAP) and is a reproducible animal model facilitating studies of the molecular mechanisms of RAP [10].
 

Biological context of Vldlr

  • In addition, the assignment of Snf212 and Vldlr to MMU19 has defined a new region of synteny between the proximal portion of the short arm of HSA9 and the mouse [11].
  • The mouse very low density lipoprotein receptor (Vldlr) gene maps to chromosome 19 [12].
  • Upregulation of liver VLDL receptor and FAT/CD36 expression in LDLR-/- apoB100/100 mice fed trans-10,cis-12 conjugated linoleic acid [13].
  • The amino acid sequence of the VLDLR is highly conserved among rabbit, human and mouse [14].
  • This receptor has been suggested to be important for the metabolism of apoprotein-E-containing triacylglycerol-rich lipoproteins, such as very-low-density-lipoprotein (VLDL), beta-migrating VLDL and intermediate-density lipoprotein. cDNA clones that code for the VLDLR were isolated from a mouse heart cDNA library [14].
  • The expression of CD105 and CD106 was significantly upregulated in the retina of adult vldlr-/- mice, especially at lesion sites. An intense CD105 signal was found in the inner retina of vldlr-/- mice starting at P14, before the onset of SNV [8].
 

Anatomical context of Vldlr

 

Associations of Vldlr with chemical compounds

  • Absence of the VLDLR resulted in a significant increase in serum triglyceride levels (1.9-fold) when mice were fed a high fat diet [15].
  • Reversal of hyperlipidaemia in apolipoprotein C1 transgenic mice by adenovirus-mediated gene delivery of the low-density-lipoprotein receptor, but not by the very-low-density-lipoprotein receptor [19].
  • These results are consistent with the hypothesis that the VLDLR and the LDLR have evolved from a common ancestral gene to play distinct roles in lipoprotein metabolism and that the metabolic handling of triacylglycerol by the body via the VLDLR is a highly conserved mechanism [14].
  • These results suggest that SRE-1 may be functional and VLDLR plays a role in cholesterol homeostasis in heart and skeletal muscle when LDLR is absent and that apo E is required for this modulation [16].
  • Reelin is a secreted glycoprotein that regulates neuronal positioning in cortical brain structures through the VLDLR and ApoER2 receptors and the adaptor protein Dab1 [4].
 

Regulatory relationships of Vldlr

  • Binding of Reelin to ApoER2 and VLDLR induces a rapid increase in tyrosine phosphorylation of Dab1, an adaptor protein that associates with the cytoplasmic domain of the receptors [20].
  • These results show that aggressive VLDL/LDL lowering achieved by hepatic overexpression of VLDLR combined with a low-fat diet regimen induces regression of advanced plaques in the brachiocephalic artery of LDL receptor-deficient mice [21].
  • IL-1beta downregulated the expression of VLDL-R in a time- and dose-dependent manner and markedly reduced the uptake of DiI-labeled beta-VLDL but not DiI-labeled low-density lipoprotein (LDL) [3].
  • In the embryonic brain, the binding of Reelin to its receptors ApoER2 and VLDLR induces subcellular events that include the activation Fyn tyrosine kinase, and plays a crucial role in cortical formation [22].
 

Other interactions of Vldlr

  • RESULTS: We show that Reelin activates members of the Src family of non-receptor tyrosine kinases (SFKs) and that this activation is dependent on the Reelin receptors apoER2 and VLDLR and the adaptor protein Dab1 [23].
  • The very low density lipoprotein receptor (VLDLR) has been proposed to play a role in the delivery of fatty acids to peripheral tissues [15].
  • Our results suggest that Reelin signaling via ApoER2, VLDLR, and Dab1 is required for the formation of a regular radial glial scaffold in the dentate gyrus [17].
  • Tracing of the mossy fibers with Phaseolus vulgaris leukoagglutinin and calbindin immunolabeling revealed an irregular broad projection in reeler mice and ApoER2/VLDLR double knockouts, likely caused by the irregular wide distribution of granule cell somata [24].
  • However, examination of mice lacking both reelin receptors, ApoER2 and VLDLR, did not reveal the same phenotype, suggesting involvement of an additional reelin-binding receptor [25].
 

Analytical, diagnostic and therapeutic context of Vldlr

References

  1. Reversal of hypercholesterolemia in low density lipoprotein receptor knockout mice by adenovirus-mediated gene transfer of the very low density lipoprotein receptor. Kobayashi, K., Oka, K., Forte, T., Ishida, B., Teng, B., Ishimura-Oka, K., Nakamuta, M., Chan, L. J. Biol. Chem. (1996) [Pubmed]
  2. Effective treatment of familial hypercholesterolaemia in the mouse model using adenovirus-mediated transfer of the VLDL receptor gene. Kozarsky, K.F., Jooss, K., Donahee, M., Strauss, J.F., Wilson, J.M. Nat. Genet. (1996) [Pubmed]
  3. Changes in cardiac lipid metabolism during sepsis: the essential role of very low-density lipoprotein receptors. Jia, L., Takahashi, M., Morimoto, H., Takahashi, S., Izawa, A., Ise, H., Iwasaki, T., Hattori, H., Wu, K.J., Ikeda, U. Cardiovasc. Res. (2006) [Pubmed]
  4. Reelin promotes hippocampal dendrite development through the VLDLR/ApoER2-Dab1 pathway. Niu, S., Renfro, A., Quattrocchi, C.C., Sheldon, M., D'Arcangelo, G. Neuron (2004) [Pubmed]
  5. Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation. Hiesberger, T., Trommsdorff, M., Howell, B.W., Goffinet, A., Mumby, M.C., Cooper, J.A., Herz, J. Neuron (1999) [Pubmed]
  6. The atherogenic lipoprotein Lp(a) is internalized and degraded in a process mediated by the VLDL receptor. Argraves, K.M., Kozarsky, K.F., Fallon, J.T., Harpel, P.C., Strickland, D.K. J. Clin. Invest. (1997) [Pubmed]
  7. Regulation of Rac1 activation by the low density lipoprotein receptor-related protein. Ma, Z., Thomas, K.S., Webb, D.J., Moravec, R., Salicioni, A.M., Mars, W.M., Gonias, S.L. J. Cell Biol. (2002) [Pubmed]
  8. Loss of VLDL receptor activates retinal vascular endothelial cells and promotes angiogenesis. Jiang, A.H., Hu, W., Meng, H., Gao, H., Qiao, X. Invest. Ophthalmol. Vis. Sci. (2008) [Pubmed]
  9. Protection from obesity in mice lacking the VLDL receptor. Goudriaan, J.R., Tacken, P.J., Dahlmans, V.E., Gijbels, M.J., van Dijk, K.W., Havekes, L.M., Jong, M.C. Arterioscler. Thromb. Vasc. Biol. (2001) [Pubmed]
  10. Expression of VLDLR in the retina and evolution of subretinal neovascularization in the knockout mouse model's retinal angiomatous proliferation. Hu, W., Jiang, A., Liang, J., Meng, H., Chang, B., Gao, H., Qiao, X. Invest. Ophthalmol. Vis. Sci. (2008) [Pubmed]
  11. Comparative mapping of 50 human chromosome 9 loci in the laboratory mouse. Pilz, A., Woodward, K., Povey, S., Abbott, C. Genomics (1995) [Pubmed]
  12. The mouse very low density lipoprotein receptor (Vldlr) gene maps to chromosome 19. Naggert, J.K., Mu, J.L. Mamm. Genome (1994) [Pubmed]
  13. Upregulation of liver VLDL receptor and FAT/CD36 expression in LDLR-/- apoB100/100 mice fed trans-10,cis-12 conjugated linoleic acid. Degrace, P., Moindrot, B., Mohamed, I., Gresti, J., Du, Z.Y., Chardigny, J.M., S??b??dio, J.L., Clouet, P. J. Lipid Res. (2006) [Pubmed]
  14. Mouse very-low-density-lipoprotein receptor (VLDLR) cDNA cloning, tissue-specific expression and evolutionary relationship with the low-density-lipoprotein receptor. Oka, K., Ishimura-Oka, K., Chu, M.J., Sullivan, M., Krushkal, J., Li, W.H., Chan, L. Eur. J. Biochem. (1994) [Pubmed]
  15. LDL receptor deficiency unmasks altered VLDL triglyceride metabolism in VLDL receptor transgenic and knockout mice. Tacken, P.J., Teusink, B., Jong, M.C., Harats, D., Havekes, L.M., van Dijk, K.W., Hofker, M.H. J. Lipid Res. (2000) [Pubmed]
  16. Mouse very low-density lipoprotein receptor (VLDLR): gene structure, tissue-specific expression and dietary and developmental regulation. Tiebel, O., Oka, K., Robinson, K., Sullivan, M., Martinez, J., Nakamuta, M., Ishimura-Oka, K., Chan, L. Atherosclerosis (1999) [Pubmed]
  17. Malformation of the radial glial scaffold in the dentate gyrus of reeler mice, scrambler mice, and ApoER2/VLDLR-deficient mice. Weiss, K.H., Johanssen, C., Tielsch, A., Herz, J., Deller, T., Frotscher, M., Förster, E. J. Comp. Neurol. (2003) [Pubmed]
  18. Identification and characterization of a very low density lipoprotein receptor-binding peptide from tissue factor pathway inhibitor that has antitumor and antiangiogenic activity. Hembrough, T.A., Ruiz, J.F., Swerdlow, B.M., Swartz, G.M., Hammers, H.J., Zhang, L., Plum, S.M., Williams, M.S., Strickland, D.K., Pribluda, V.S. Blood (2004) [Pubmed]
  19. Reversal of hyperlipidaemia in apolipoprotein C1 transgenic mice by adenovirus-mediated gene delivery of the low-density-lipoprotein receptor, but not by the very-low-density-lipoprotein receptor. Jong, M.C., van Dijk, K.W., Dahlmans, V.E., Van der Boom, H., Kobayashi, K., Oka, K., Siest, G., Chan, L., Hofker, M.H., Havekes, L.M. Biochem. J. (1999) [Pubmed]
  20. Binding of purified Reelin to ApoER2 and VLDLR mediates tyrosine phosphorylation of Disabled-1. Benhayon, D., Magdaleno, S., Curran, T. Brain Res. Mol. Brain Res. (2003) [Pubmed]
  21. Aggressive very low-density lipoprotein (VLDL) and LDL lowering by gene transfer of the VLDL receptor combined with a low-fat diet regimen induces regression and reduces macrophage content in advanced atherosclerotic lesions in LDL receptor-deficient mice. MacDougall, E.D., Kramer, F., Polinsky, P., Barnhart, S., Askari, B., Johansson, F., Varon, R., Rosenfeld, M.E., Oka, K., Chan, L., Schwartz, S.M., Bornfeldt, K.E. Am. J. Pathol. (2006) [Pubmed]
  22. NMDA-receptor proteins are upregulated in the hippocampus of postnatal heterozygous reeler mice. Isosaka, T., Hattori, K., Yagi, T. Brain Res. (2006) [Pubmed]
  23. Reelin activates SRC family tyrosine kinases in neurons. Bock, H.H., Herz, J. Curr. Biol. (2003) [Pubmed]
  24. Dentate granule cells in reeler mutants and VLDLR and ApoER2 knockout mice. Drakew, A., Deller, T., Heimrich, B., Gebhardt, C., Del Turco, D., Tielsch, A., Förster, E., Herz, J., Frotscher, M. Exp. Neurol. (2002) [Pubmed]
  25. Reelin signaling is necessary for a specific step in the migration of hindbrain efferent neurons. Rossel, M., Loulier, K., Feuillet, C., Alonso, S., Carroll, P. Development (2005) [Pubmed]
  26. Differential binding of ligands to the apolipoprotein E receptor 2. Andersen, O.M., Benhayon, D., Curran, T., Willnow, T.E. Biochemistry (2003) [Pubmed]
  27. Expression of the VLDL receptor in endothelial cells. Wyne, K.L., Pathak, K., Seabra, M.C., Hobbs, H.H. Arterioscler. Thromb. Vasc. Biol. (1996) [Pubmed]
  28. Role of VLDL receptor in the process of foam cell formation. Qu, S., Wu, F., Tian, J., Li, Y., Wang, Y., Wang, Y., Zong, Y. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban. (2004) [Pubmed]
 
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