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Gene Review

LDLR  -  low density lipoprotein receptor

Homo sapiens

Synonyms: FH, FHC, LDL receptor, LDLCQ2, Low-density lipoprotein receptor
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Disease relevance of LDLR

  • In addition, control, LDLR(-/-), and LDLR(-/-)/APOC1 mice were transfected with adenovirus carrying the gene for the receptor-associated protein (Ad-RAP) [1].
  • We previously reported that testosterone attenuated atherogenesis in LDLR(-/-) male mice, and that this effect of testosterone was most likely caused by its conversion to estradiol [2].
  • Mutations in the LDLr gene (LDLR), which is located on chromosome 19, cause familial hypercholesterolemia (FH), an autosomal dominant disorder characterized by severe hypercholesterolemia associated with premature coronary atherosclerosis [3].
  • Although plaque ruptures/deep erosions were far less frequent than in human populations, these observations demonstrate that spontaneous plaque rupture and secondary thrombosis do occur in apoE(-/-) and LDLR(-/-) mice [4].
  • In all myopathies, a subset of regenerating and necrotizing muscle fibers had prominent diffuse accumulation of both LDLR and free cholesterol [5].

Psychiatry related information on LDLR


High impact information on LDLR

  • The low-density lipoprotein receptor (LDLR) is responsible for uptake of cholesterol-carrying lipoprotein particles into cells [11].
  • The LDL receptor-related protein LRP6 mediates internalization and lethality of anthrax toxin [12].
  • Mutations in the genes encoding either LDLR or its ligand (APOB) cause severe hypercholesterolemia [13].
  • These mutations are probably gain-of-function mutations, as overexpression of PCSK9 in the liver of mice produces hypercholesterolemia by reducing LDLR number [13].
  • A novel cellular phenotype for familial hypercholesterolemia due to a defect in polarized targeting of LDL receptor [14].

Chemical compound and disease context of LDLR


Biological context of LDLR

  • Functional studies on the LDLR pathway showed that SNX17 enhances the endocytosis rate of this receptor [19].
  • 3. This result concurs with and extends a previous study in which LDLR was mapped to chromosome 19 by screening somatic cell hybrids with a species-specific monoclonal antibody [20].
  • The amino acid sequences of tryptic peptides showed identity with the human low density lipoprotein (LDL) receptor (LDLR) [21].
  • This represents a previously unrecognized link between LDLR and hemostasis [22].
  • Our previous studies showed that mutations within the repeat 3 sequence of the LDLR promoter significantly decreased OM activity on LDLR promoter luciferase reporter constructs that contain the sterol responsive element-1 (repeat 2) and Sp1 binding sites (repeats 1 and 3) [23].

Anatomical context of LDLR

  • ARH appears to have a tissue-specific role in LDLR function, as it is required in liver but not in fibroblasts [24].
  • The PCSK9-induced degradation of the LDLR was shown to require transport out of the endoplasmic reticulum [25].
  • Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment [25].
  • Biochemical assays and quantification of LDLR by electron microscopy indicated that ARH-/- lymphocytes had >20-fold more LDLR on the cell surface and a approximately 27-fold excess of LDLR outside of coated pits [26].
  • To determine the physiological relevance of these interactions, we examined the effect of mutations in the ARH on LDLR location and function in polarized hepatocytes (WIF-B) [27].

Associations of LDLR with chemical compounds

  • The low-density lipoprotein receptor (LDLR) is responsible for the uptake of cholesterol-containing lipoprotein particles into cells [28].
  • The PCSK9-induced degradation of the LDLR was not affected by inhibitors of the proteasome, lysosomal cysteine proteases, aspartic acid proteases, or metalloproteases [25].
  • Oncostatin M (OM) activates the transcription of the human low density lipoprotein receptor (LDLR) in HepG2 cells through a sterol-independent mechanism [23].
  • The phosphotyrosine binding domain of ARH interacted with the internalization sequence (NPVY) in the cytoplasmic tail of LDLR in a sequence-specific manner [29].
  • Uptake was reduced by the known LRP1 inhibitors RAP, lactoferrin, and suramin, but not by LDL, which exclusively binds to the LDLR [30].

Physical interactions of LDLR

  • ApoE is able to interact with the LDL receptor only when it is bound to lipid particles [31].
  • Mutations in the NPVY sequence that were previously shown to decrease LDLR internalization abolished in vitro binding to ARH [29].
  • In addition, LPL enhances the binding in LDL-receptor negative fibroblasts to the same extent as it does in normal fibroblasts [32].
  • Here, we show that treating HepG2 cells with OM specifically leads to prominent increases of the levels of c/EBPbeta and Egr1 bound to the LDLR promoter in vivo [33].
  • The availability of pure OVR and LDLR enable us to determine kinetic parameters for the binding of RAP and lactoferrin to these receptors by surface plasmon resonance [34].

Enzymatic interactions of LDLR


Regulatory relationships of LDLR

  • Taken together, we provide strong evidence that Egr1 regulates LDLR transcription via a novel mechanism of protein-protein interaction with c/EBPbeta [33].
  • Promoter deletion and mutation studies showed that the AP-1 binding sites were essential for LDL-IC-stimulated LDLR expression [37].
  • This finding supports the hypothesis that the impact of genetic defects at the low density lipoprotein receptor (LDLR) locus in FH subjects prevails over any influence on the part of ApoE polymorphism [38].
  • OM (oncostatin M) activates the human LDLR [LDL (low-density lipoprotein) receptor] gene transcription in HepG2 cells through the SIRE (sterol-independent regulatory element) of LDLR promoter [39].
  • These data provide an alternative mechanism of LDL receptor gene expression by non-classical estradiol- and tamoxifen-stimulated induction through an ER-alpha/Sp1 complex [40].

Other interactions of LDLR

  • Using beta-migrating very low density lipoproteins (beta-VLDLs), known as a good ligand for LRP, binding studies were performed on LDL receptor-negative human fibroblasts [41].
  • Evidence for linkage was observed at the MnSOD (P=.02), CETP/LCAT (P=.03), and apolipoprotein AI-CIII-AIV loci (P=.005) but not at the LDLR locus [42].
  • The virus associates with serum lipoproteins, including those containing apolipoprotein E (apoE) and apolipoprotein B (apoB), and may enter cells via the low-density lipoprotein receptor (LDLR) [43].
  • SUMMARY: The available data suggest that ARH functions as an adaptor protein that couples LDLR to the endocytic machinery [44].
  • A novel domain containing a FERM-like domain of SNX17 is needed for its interaction with the LDL receptor [45].

Analytical, diagnostic and therapeutic context of LDLR

  • The structure of ligand-binding repeat 5 (LR5) of the LDLR, determined to 1.7 A resolution by X-ray crystallography and presented here, contains a calcium ion coordinated by acidic residues that lie at the carboxy-terminal end of the domain and are conserved among LDL-A modules [28].
  • Regulation of LDLR expression by LDL was compared between the human normal and cancer prostate cells using semi-quantitative RT-PCR and LDL uptake assays [46].
  • Autosomal dominant (AD) familial hypercholesterolemia [FH; Mendelian Inheritance in Man (MIM) 143890] typically results from mutations in the LDL receptor gene (LDLR), which are now commonly diagnosed using exon-by-exon screening methods, such as exon-by-exon sequence analysis (EBESA) of genomic DNA (gDNA) [47].
  • The localization of HA, p75-NTR, and LDLR was determined by confocal microscopy [48].
  • The objective of this work was to develop a DNA array for large-scale identification of mutant LDLR alleles [49].


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  11. Structure and physiologic function of the low-density lipoprotein receptor. Jeon, H., Blacklow, S.C. Annu. Rev. Biochem. (2005) [Pubmed]
  12. The LDL receptor-related protein LRP6 mediates internalization and lethality of anthrax toxin. Wei, W., Lu, Q., Chaudry, G.J., Leppla, S.H., Cohen, S.N. Cell (2006) [Pubmed]
  13. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Cohen, J., Pertsemlidis, A., Kotowski, I.K., Graham, R., Garcia, C.K., Hobbs, H.H. Nat. Genet. (2005) [Pubmed]
  14. A novel cellular phenotype for familial hypercholesterolemia due to a defect in polarized targeting of LDL receptor. Koivisto, U.M., Hubbard, A.L., Mellman, I. Cell (2001) [Pubmed]
  15. Modulation of the LDL receptor and LRP levels by HIV protease inhibitors. Tran, H., Robinson, S., Mikhailenko, I., Strickland, D.K. J. Lipid Res. (2003) [Pubmed]
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  20. Human genes involved in cholesterol metabolism: chromosomal mapping of the loci for the low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl-coenzyme A reductase with cDNA probes. Lindgren, V., Luskey, K.L., Russell, D.W., Francke, U. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
  21. Members of the low density lipoprotein receptor family mediate cell entry of a minor-group common cold virus. Hofer, F., Gruenberger, M., Kowalski, H., Machat, H., Huettinger, M., Kuechler, E., Blass, D. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  22. LDL receptor cooperates with LDL receptor-related protein in regulating plasma levels of coagulation factor VIII in vivo. Bovenschen, N., Mertens, K., Hu, L., Havekes, L.M., van Vlijmen, B.J. Blood (2005) [Pubmed]
  23. Induction of low density lipoprotein receptor (LDLR) transcription by oncostatin M is mediated by the extracellular signal-regulated kinase signaling pathway and the repeat 3 element of the LDLR promoter. Li, C., Kraemer, F.B., Ahlborn, T.E., Liu, J. J. Biol. Chem. (1999) [Pubmed]
  24. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Garcia, C.K., Wilund, K., Arca, M., Zuliani, G., Fellin, R., Maioli, M., Calandra, S., Bertolini, S., Cossu, F., Grishin, N., Barnes, R., Cohen, J.C., Hobbs, H.H. Science (2001) [Pubmed]
  25. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Maxwell, K.N., Fisher, E.A., Breslow, J.L. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  26. The modular adaptor protein ARH is required for low density lipoprotein (LDL) binding and internalization but not for LDL receptor clustering in coated pits. Michaely, P., Li, W.P., Anderson, R.G., Cohen, J.C., Hobbs, H.H. J. Biol. Chem. (2004) [Pubmed]
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  29. ARH is a modular adaptor protein that interacts with the LDL receptor, clathrin, and AP-2. He, G., Gupta, S., Yi, M., Michaely, P., Hobbs, H.H., Cohen, J.C. J. Biol. Chem. (2002) [Pubmed]
  30. Expression of LRP1 by human osteoblasts: a mechanism for the delivery of lipoproteins and vitamin K1 to bone. Niemeier, A., Kassem, M., Toedter, K., Wendt, D., Ruether, W., Beisiegel, U., Heeren, J. J. Bone Miner. Res. (2005) [Pubmed]
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