Disease relevance of Ldlr

• To investigate whether in vivo exposure to pneumococci can affect atherogenesis, we immunized Ldlr(-/-) mice with Streptococcus pneumoniae [1].
• These results demonstrate that increased expression of G5 and G8 attenuates diet-induced hypercholesterolemia in Ldlr-/- mice, resulting in a significant reduction in plasma levels of cholesterol and aortic atherosclerotic lesion area [2].
• Previously we showed L-4F, a novel apolipoprotein A-I (apoA-I) mimetic, improved vasodilation in 2 dissimilar models of vascular disease: hypercholesterolemic LDL receptor-null (Ldlr(-/-)) mice and transgenic sickle cell disease mice [3].
• Targeted gene disruption or overexpression of 12/15-lipoxygenase in mice on the genetic background of apolipoprotein E or low density lipoprotein-receptor (LDL-R) deficiency has implicated 12/15-lipoxygenase in atherogenesis [4].
• Severe hypercholesterolemia, hypertriglyceridemia, and atherosclerosis in mice lacking both leptin and the low density lipoprotein receptor [5].

High impact information on Ldlr

• The low-density lipoprotein receptor (LDLR) prevents hypercholesterolemia and atherosclerosis by removing low-density lipoprotein (LDL) from circulation [6].
• A receptor for subgroup A Rous sarcoma virus is related to the low density lipoprotein receptor [7].
• Correction: LDL receptor-related protein internalizes and degrades uPA-PAI-1 complexes and is essential for embryo implantation [8].
• Overexpression of apoM in Ldlr(-/-) mice protected against atherosclerosis when the mice were challenged with a cholesterol-enriched diet, showing that apoM is important for the formation of prebeta-HDL and cholesterol efflux to HDL, and thereby inhibits formation of atherosclerotic lesions [9].
• Dexamethasone induction of hypertension and diabetes is PPAR-alpha dependent in LDL receptor-null mice [10].

Chemical compound and disease context of Ldlr

• In HepG2 human hepatoma cells, naringenin inhibits apolipoprotein B (apoB) secretion primarily by inhibiting microsomal triglyceride transfer protein and enhances LDL receptor (LDLr)-mediated apoB-containing lipoprotein uptake [11].
• Wild-type (C57BL/6) mice and mice deficient for the low density lipoprotein receptor (LDLR-/-) or apolipoprotein E (apoE-/-) were fed a low fat, rodent chow diet or a high fat, high sucrose (diabetogenic) diet to induce obesity [12].
• Fenofibrate prevents obesity and hypertriglyceridemia in low-density lipoprotein receptor-null mice [13].
• We investigated the effect of increased plasma concentrations of low-density-lipoproteins (LDL) on survival and cytokine production after a lethal challenge with either LPS or live Gram-negative bacteria in LDL receptor deficient mice (LDLR-/-) [14].
• The effects of testosterone on early atherogenesis and the role of aromatase, an enzyme that converts testosterone to estrogens, were assessed in low density lipoprotein receptor-deficient male mice fed a Western diet [15].

Biological context of Ldlr

• Localization of atherosclerosis susceptibility loci to chromosomes 4 and 6 using the Ldlr knockout mouse model [16].
• To determine whether increased expression of G5 and G8 can ameliorate hypercholesterolemia in mice lacking LDL receptors (LDLRs), we examined the effects of G5G8 transgene expression on cholesterol metabolism and atherosclerosis in Ldlr-/- mice [2].
• Histopathology showed an increase in macrophage and hepatocyte lipids independent of Ldlr genotype [17].
• The inhibition of NO production was caused by the suppression of inducible nitric oxide synthase (iNOS) gene expression in peritoneal macrophages isolated from Ldlr-/- mice [18].
• Here we determine the mechanisms by which D-4F improves vasodilation and arterial wall thickness in hypercholesterolemic Ldlr(-/-) mice and Ldlr(-/-)/apoA-I null (apoA-I(-/-)), double-knockout mice [3].

Anatomical context of Ldlr

• Ldlr(-/-) hepatocytes secreted apoB100 at a 3.5-fold higher rate than did wild-type hepatocytes [19].
• A significant reduction in atherosclerotic lesions was also demonstrated in AD-fed, low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice reconstituted with CD1d(-/-) bone marrow cells compared with the lesions observed in Ldlr(-/-)mice reconstituted with WT marrow cells [20].
• Primary cultured peritoneal macrophages from Ldlr-/- mice showed increased level of TNF-alpha andIL-1beta mRNA in response to treatment with lipopolysaccharide; these increases were inhibited by co-treatment with tilianin [21].
• Hematein treatment inhibited NF-kappaB-DNA binding activity in peritoneal macrophages from Ldlr-/- mice and the activation of NF-kappaB in RAW264.7 macrophages [22].
• We report that the low density lipoprotein receptor (LDLR) regulates the cellular uptake and central nervous system levels of astrocyte-derived apoE [23].

Associations of Ldlr with chemical compounds

• Thus, on day 5, plasma corticosterone levels were reduced by 57, 70, and 73% (all P < 0.05) and on day 8 by 76, 59, and 63% (all P < 0.05) in hl(-/-), Ldlr(-/-), and Ldlr(-/-)hl(-/-) mice, respectively [24].
• This compound suppressed plasma nitrite/nitrate levels in Ldlr-/- mice and NO production and iNOS expression in LPS+IFNgamma-stimulated peritoneal macrophages [22].
• METHODS AND RESULTS: In low-density lipoprotein (LDL) receptor-deficient (Ldlr(-/-)) mice fed an atherogenic diet for 4 or 8 weeks, trichostatin A (TSA), a specific histone deacetylase inhibitor, exacerbated atherosclerosis without alteration on plasma lipid profiles [25].
• Our findings suggest that an extrahepatic RAP-sensitive process that is independent of the LDLR or LRP is involved in metabolism of triglyceride-rich lipoproteins [26].
• These results indicate that the LDLR constitutes the major pathway for the clearance of retinyl ester [27].

Physical interactions of Ldlr

• Structure of a monoclonal 2E8 Fab antibody fragment specific for the low-density lipoprotein-receptor binding region of apolipoprotein E refined at 1.9 A [28].
• Sequence of the putative low-density lipoprotein receptor-binding regions of apolipoprotein B in mouse and hamster [29].
• Identification and characterization of a very low density lipoprotein receptor-binding peptide from tissue factor pathway inhibitor that has antitumor and antiangiogenic activity [30].
• The production of functional LDL receptor was confirmed by ligand binding of DiI-LDL cholesterol [31].
• The receptor-associated protein, RAP, is a chaperonin-like molecule that binds to two members of the low density lipoprotein receptor (LDLR) superfamily-megalin (gp330) and the LDL receptor-related protein (LRP) [32].

Enzymatic interactions of Ldlr

• Our studies showed an altered LDLr expression and altered phosphorylated MAPK in the liver of C57BL/6 mice during aging [33].
• PPARgamma regulates adipocyte cholesterol metabolism via oxidized LDL receptor 1 [34].

Regulatory relationships of Ldlr

• ApoE(-/-) mice exhibited a higher susceptibility to virus-induced immunopathology than LDLR(-/-) mice and usually succumbed to immunopathologic disease when infected with high doses of virus [35].
• Reduced connexin43 expression inhibits atherosclerotic lesion formation in low-density lipoprotein receptor-deficient mice [36].
• B7-1/B7-2 costimulation regulates plaque antigen-specific T-cell responses and atherogenesis in low-density lipoprotein receptor-deficient mice [37].
• The cloning of the Ldlr gene will enhance the usefulness of the mouse for the study of cholesterol metabolism and, in particular, for carrying out gene targeting experiments [38].
• Macrophage lipoprotein lipase promotes foam cell formation and atherosclerosis in low density lipoprotein receptor-deficient mice [39].

Other interactions of Ldlr

• Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice [40].
• Cholesterol lowering in low density lipoprotein receptor knockout mice overexpressing apolipoprotein E [41].
• Thus, the capacity of leukocytes to express mIL-8RH, and associated intralesional expression of its ligands such as KC/GROalpha, mediated the intimal accumulation of macrophages in atherosclerotic lesions of LDL receptor-deficient mice [42].
• The very low density lipoprotein receptor (VLDLR) has been proposed to play a role in the delivery of fatty acids to peripheral tissues [43].
• In summary, testosterone deficiency increased plasma levels of apolipoprotein B-containing lipoproteins (apoB-LPs) and anti-OxLDL antibodies, decreased LDL receptor affinity, and doubled the size of diet-induced atherosclerotic lesions [44].

Analytical, diagnostic and therapeutic context of Ldlr

• To study this, chylomicron remnants labeled with a fluorescent dye were perfused into isolated livers of LDL receptor-deficient (LDLR-deficient) mice (Ldlr(-/-)) and examined by confocal microscopy [45].
• We have used the Ldlr knockout mouse model in an interspecific genetic cross to map atherosclerosis susceptibility loci [16].
• In support of this, agarose gel electrophoresis revealed that an oral fat load resulted in retention of chylomicrons in the LDLR(-/-) mice, which was not seen in wild-type mice [27].
• We conclude that apoE liposomes enable LDL receptor-mediated specific delivery of antineoplastic (pro)drugs to tumours, and, therefore, constitute an attractive novel option for anti-tumour chemotherapy [46].
• METHODS AND RESULTS: Chimeras that specifically overexpress ABCA1 in macrophages were generated by transplantation of bone marrow from human ABCA1 bacterial artificial chromosome (BAC) transgenic mice into LDLr-/- mice [47].

References