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Journal articles on the topic 'LDLrKO'
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1
Dupasquier, Chantal M. C., Elena Dibrov, Annette L. Kneesh, Paul K. M. Cheung, Kaitlin G. Y. Lee, Helen K. Alexander, Behzad K. Yeganeh, Mohammed H. Moghadasian, and Grant N. Pierce. "Dietary flaxseed inhibits atherosclerosis in the LDL receptor-deficient mouse in part through antiproliferative and anti-inflammatory actions." American Journal of Physiology-Heart and Circulatory Physiology 293, no. 4 (October 2007): H2394—H2402. http://dx.doi.org/10.1152/ajpheart.01104.2006.
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Dietary flaxseed has been shown to have potent antiatherogenic effects in rabbits. The purpose of the present study was to investigate the antiatherogenic capacity of flaxseed in an animal model that more closely represents the human atherosclerotic condition, the LDL receptor-deficient mouse (LDLrKO), and to identify the cellular mechanisms for these effects. LDLrKO mice were administered a regular diet (RG), a 10% flaxseed-supplemented diet (FX), or an atherogenic diet containing 2% cholesterol alone (CH) or supplemented with 10% flaxseed (CF), 5% flaxseed (CF5), 1% flaxseed (CF1), or 5% coconut oil (CS) for 24 wk. LDLrKO mice fed a cholesterol-supplemented diet exhibited a rise in plasma cholesterol without a change in triglycerides and an increase in atherosclerotic plaque formation. The CS mice exhibited elevated levels of plasma cholesterol, triglycerides, and saturated fatty acids and an increase in plaque development. Supplementation of the cholesterol-enriched diet with 10% (wt/wt) ground flaxseed lowered plasma cholesterol and saturated fatty acids, increased plasma ALA, and inhibited plaque formation in the aorta and aortic sinus compared with mice fed a diet supplemented with only dietary cholesterol. The expression of proliferating cell nuclear antigen (PCNA) and the inflammatory markers IL-6, mac-3, and VCAM-1 was increased in aortic tissue from CH and CS mice. This expression was significantly reduced or normalized when flaxseed was included in the diet. Our results demonstrate that dietary flaxseed can inhibit atherosclerosis in the LDLrKO mouse through a reduction of circulating cholesterol levels and, at a cellular level, via antiproliferative and anti-inflammatory actions.
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Forrest, Lolita M., Elena Boudyguina, Martha D. Wilson, and John S. Parks. "Echium oil reduces atherosclerosis in apoB100-only LDLrKO mice." Atherosclerosis 220, no. 1 (January 2012): 118–21. http://dx.doi.org/10.1016/j.atherosclerosis.2011.10.025.
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Cao, Qiang, Xin Cui, Rui Wu, Lin Zha, Xianfeng Wang, John S. Parks, Liqing Yu, Hang Shi, and Bingzhong Xue. "Myeloid Deletion of α1AMPK Exacerbates Atherosclerosis in LDL Receptor Knockout (LDLRKO) Mice." Diabetes 65, no. 6 (January 28, 2016): 1565–76. http://dx.doi.org/10.2337/db15-0917.
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Bi, Xin, Xuewei Zhu, MyNgan Duong, Elena Y. Boudyguina, Martha D. Wilson, Abraham K. Gebre, and John S. Parks. "Liver ABCA1 Deletion in LDLrKO Mice Does Not Impair Macrophage Reverse Cholesterol Transport or Exacerbate Atherogenesis." Arteriosclerosis, Thrombosis, and Vascular Biology 33, no. 10 (October 2013): 2288–96. http://dx.doi.org/10.1161/atvbaha.112.301110.
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Baumgartner, Roland, Felipe B. Casagrande, Randi B. Mikkelsen, Martin Berg, Konstantinos A. Polyzos, Maria J. Forteza, Aastha Arora, Thue W. Schwartz, Siv A. Hjorth, and Daniel F. J. Ketelhuth. "Disruption of GPR35 Signaling in Bone Marrow-Derived Cells Does Not Influence Vascular Inflammation and Atherosclerosis in Hyperlipidemic Mice." Metabolites 11, no. 7 (June 23, 2021): 411. http://dx.doi.org/10.3390/metabo11070411.
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G-protein-coupled receptor-35 (GPR35) has been identified as a receptor for the tryptophan metabolite kynurenic acid (KynA) and suggested to modulate macrophage polarization in metabolic tissues. Whether GPR35 can influence vascular inflammation and atherosclerosis has however never been tested. Lethally irradiated LdlrKO mice were randomized to receive GPR35KO or wild type (WT) bone marrow transplants and fed a high cholesterol diet for eight weeks to develop atherosclerosis. GPR35KO and WT chimeric mice presented no difference in the size of atherosclerotic lesions in the aortic arch (2.37 ± 0.58% vs. 1.95 ± 0.46%, respectively) or in the aortic roots (14.77 ± 3.33% vs. 11.57 ± 2.49%, respectively). In line with these data, no changes in the percentage of VCAM-1+, IAb + cells, and CD3+ T cells, as well as alpha smooth muscle cell actin expression, was observed between groups. Interestingly, the GPR35KO group presented a small but significant increase in CD68+ macrophage infiltration in the plaque. However, in vitro culture experiments using bone marrow-derived macrophages from both groups indicated that GPR35 plays no role in modulating the secretion of major inflammatory cytokines. Our study indicates that GPR35 expression does not play a direct role in macrophage activation, vascular inflammation, and the development of atherosclerosis.
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Schaftenaar, Frank, Jacob Amersfoort, Hidde Douna, Mara Kröner, Bram Slütter, Ilze Bot, Gijs van Puijvelde, and Johan Kuiper. "Vaccination with ApoB100 Derived HLA-A2 Restricted CD8 T Cell Epitopes Did Not Reduce Atherosclerosis in Male LDLrKO hApoB100tg HLA-A2tg Mice." Atherosclerosis Supplements 32 (June 2018): 100–101. http://dx.doi.org/10.1016/j.atherosclerosissup.2018.04.307.
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Jasiecki, Jacek, Monika Targońska, Anna Janaszak-Jasiecka, Magdalena Chmara, Monika Żuk, Leszek Kalinowski, Krzysztof Waleron, and Bartosz Wasąg. "Novel Tools for Comprehensive Functional Analysis of LDLR (Low-Density Lipoprotein Receptor) Variants." International Journal of Molecular Sciences 24, no. 14 (July 14, 2023): 11435. http://dx.doi.org/10.3390/ijms241411435.
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Familial hypercholesterolemia (FH) is an autosomal-dominant disorder caused mainly by substitutions in the low-density lipoprotein receptor (LDLR) gene, leading to an increased risk of premature cardiovascular diseases. Tremendous advances in sequencing techniques have resulted in the discovery of more than 3000 variants of the LDLR gene, but not all of them are clinically relevant. Therefore, functional studies of selected variants are needed for their proper classification. Here, a single-cell, kinetic, fluorescent LDL uptake assay was applied for the functional analysis of LDLR variants in a model of an LDLR-deficient human cell line. An LDLR-defective HEK293T cell line was established via a CRISPR/Cas9-mediated luciferase–puromycin knock-in. The expressing vector with the LDLR gene under the control of the regulated promoter and with a reporter gene has been designed to overproduce LDLR variants in the host cell. Moreover, an LDLR promoter–luciferase knock-in reporter system has been created in the human cell line to study transcriptional regulation of the LDLR gene, which can serve as a simple tool for screening and testing new HMG CoA reductase-inhibiting drugs for atherosclerosis therapy. The data presented here demonstrate that the obtained LDLR-deficient human cell line HEK293T-ldlrG1 and the dedicated pTetRedLDLRwt expression vector are valuable tools for studying LDL internalization and functional analysis of LDLR and its genetic variants. Using appropriate equipment, LDL uptake to a single cell can be measured in real time. Moreover, the luciferase gene knock-in downstream of the LDLR promotor allows the study of promoter regulation in response to diverse conditions or drugs. An analysis of four known LDLR variants previously classified as pathogenic and benign was performed to validate the LDLR-expressing system described herein with the dedicated LDLR-deficient human cell line, HEK293T-ldlrG1.
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Strøm, Thea Bismo, Katrine Bjune, Luís Teixeira da Costa, and Trond P. Leren. "Strategies to prevent cleavage of the linker region between ligand-binding repeats 4 and 5 of the LDL receptor." Human Molecular Genetics 28, no. 22 (July 23, 2019): 3734–41. http://dx.doi.org/10.1093/hmg/ddz164.
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Abstract A main strategy for lowering plasma low-density lipoprotein (LDL) cholesterol levels is to increase the number of cell-surface LDL receptors (LDLRs). This can be achieved by increasing the synthesis or preventing the degradation of the LDLR. One mechanism by which an LDLR becomes non-functional is enzymatic cleavage within the 10 residue linker region between ligand-binding repeats 4 and 5. The cleaved LDLR has only three ligand-binding repeats and is unable to bind LDL. In this study, we have performed cell culture experiments to identify strategies to prevent this cleavage. As a part of these studies, we found that Asp193 within the linker region is critical for cleavage to occur. Moreover, both 14-mer synthetic peptides and antibodies directed against the linker region prevented cleavage. As a consequence, more functional LDLRs were observed on the cell surface. The observation that the cleaved LDLR was present in extracts from the human adrenal gland indicates that cleavage of the linker region takes place in vivo. Thus, preventing cleavage of the LDLR by pharmacological measures could represent a novel lipid-lowering strategy.
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Persson, Lena, Cecilia Gälman, Bo Angelin, and Mats Rudling. "Importance of Proprotein Convertase Subtilisin/Kexin Type 9 in the Hormonal and Dietary Regulation of Rat Liver Low-Density Lipoprotein Receptors." Endocrinology 150, no. 3 (November 13, 2008): 1140–46. http://dx.doi.org/10.1210/en.2008-1281.
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Hormonal or dietary challenge can stimulate hepatic low-density lipoprotein receptor (LDLR) expression through posttranscriptional mechanisms. We here tested whether such observations may be due to regulation of proprotein convertase subtilisin/kexin type 9 (PCSK9). Treatment with glucagon resulted in a 2-fold increase in hepatic LDLR protein expression, whereas its mRNA levels were reduced; this occurred simultaneously with a 70% reduction in PCSK9 expression. Insulin treatment resulted in responses opposite to those seen by treatment with glucagon. Furthermore, high-dose ethinylestradiol treatment reduced PCSK9 expression by half. Finally, feeding of rats with dietary cholesterol reduced PCSK9 expression, resulting in an increased number of hepatic LDLRs despite a reduction of LDLR mRNA levels. Regulation of PCSK9 occurred in part through sterol regulatory element binding protein-2, but changes in this cholesterol-controlled transcription factor could not explain all hormonal effects seen. We conclude that the hormonal and dietary regulation of hepatic LDLRs also involves posttranscriptional regulation by PCSK9. The identification of PCSK9 regulation by these various treatments is important in understanding of the physiological function of this protein and points to new targets for therapeutic treatments to increase hepatic LDLR numbers. PCSK9, which reduces LDL-receptors by posttranscriptional mechanisms, is involved in the hormonal stimulation of LDL receptors by glucagon and estrogens.
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Kim, Meewhi, and Ilya Bezprozvanny. "Differences in Recycling of Apolipoprotein E3 and E4—LDL Receptor Complexes—A Mechanistic Hypothesis." International Journal of Molecular Sciences 22, no. 9 (May 10, 2021): 5030. http://dx.doi.org/10.3390/ijms22095030.
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Apolipoprotein E (ApoE) is a protein that plays an important role in the transport of fatty acids and cholesterol and in cellular signaling. On the surface of the cells, ApoE lipoparticles bind to low density lipoprotein receptors (LDLR) that mediate the uptake of the lipids and downstream signaling events. There are three alleles of the human ApoE gene. Presence of ApoE4 allele is a major risk factor for developing Alzheimer’s disease (AD) and other disorders late in life, but the mechanisms responsible for biological differences between different ApoE isoforms are not well understood. We here propose that the differences between ApoE isoforms can be explained by differences in the pH-dependence of the association between ApoE3 and ApoE4 isoforms and LDL-A repeats of LDLR. As a result, the following endocytosis ApoE3-associated LDLRs are recycled back to the plasma membrane but ApoE4-containing LDLR complexes are trapped in late endosomes and targeted for degradation. The proposed mechanism is predicted to lead to a reduction in steady-state surface levels of LDLRs and impaired cellular signaling in ApoE4-expressing cells. We hope that this proposal will stimulate experimental research in this direction that allows the testing of our hypothesis.
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Kang, Richard S., and Heike Fölsch. "ARH cooperates with AP-1B in the exocytosis of LDLR in polarized epithelial cells." Journal of Cell Biology 193, no. 1 (March 28, 2011): 51–60. http://dx.doi.org/10.1083/jcb.201012121.
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The autosomal recessive hypercholesterolemia protein (ARH) is well known for its role in clathrin-mediated endocytosis of low-density lipoprotein receptors (LDLRs). During uptake, ARH directly binds to the FxNPxY signal in the cytoplasmic tail of LDLR. Interestingly, the same FxNPxY motif is used in basolateral exocytosis of LDLR from recycling endosomes (REs), which is facilitated by the epithelial-specific clathrin adaptor AP-1B. However, AP-1B directly interacts with neither the FxNPxY motif nor the second more distally located YxxØ sorting motif of LDLR. Here, we show that ARH colocalizes and cooperates with AP-1B in REs. Knockdown of ARH in polarized epithelial cells leads to specific apical missorting of truncated LDLR, which encodes only the FxNPxY motif (LDLR-CT27). Moreover, a mutation in ARH designed to disrupt the interaction of ARH with AP-1B specifically abrogates exocytosis of LDLR-CT27. We conclude that in addition to its role in endocytosis, ARH cooperates with AP-1B in basolateral exocytosis of LDLR from REs.
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Lin, Jean Z., Alexandro J. Martagón, Willa A. Hsueh, John D. Baxter, Jan-Åke Gustafsson, Paul Webb, and Kevin J. Phillips. "Thyroid Hormone Receptor Agonists Reduce Serum Cholesterol Independent of the LDL Receptor." Endocrinology 153, no. 12 (December 1, 2012): 6136–44. http://dx.doi.org/10.1210/en.2011-2081.
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Abstract The majority of cholesterol reduction therapies, such as the statin drugs, work primarily by inducing the expression of hepatic low-density lipoprotein receptors (LDLRs), rendering these therapeutics only partially effective in animals lacking LDLRs. Although thyroid hormones and their synthetic derivatives, often referred to as thyromimetics, have been clearly shown to reduce serum cholesterol levels, this action has generally been attributed to their ability to increase expression of hepatic LDLRs. Here we show for the first time that the thyroid hormone T3 and the thyroid hormone receptor-β selective agonists GC-1 and KB2115 are capable of markedly reducing serum cholesterol in mice devoid of functional LDLRs by inducing Cyp7a1 expression and stimulating the conversion and excretion of cholesterol as bile acids. Based on this LDLR-independent mechanism, thyromimetics such as GC-1 and KB2115 may represent promising cholesterol-lowering therapeutics for the treatment of diseases such as homozygous familial hypercholesterolemia, a rare genetic disorder caused by a complete lack of functional LDLRs, for which there are limited treatment options because most therapeutics are only minimally effective.
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Konecsni, Tuende, Ursula Berka, Angela Pickl-Herk, Gerhard Bilek, Abdul Ghafoor Khan, Leszek Gajdzig, Renate Fuchs, and Dieter Blaas. "Low pH-Triggered Beta-Propeller Switch of the Low-Density Lipoprotein Receptor Assists Rhinovirus Infection." Journal of Virology 83, no. 21 (August 12, 2009): 10922–30. http://dx.doi.org/10.1128/jvi.01312-09.
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ABSTRACT Minor group human rhinoviruses (HRVs) bind three members of the low-density lipoprotein receptor (LDLR) family: LDLR proper, very-LDLR (VLDLR) and LDLR-related protein (LRP). Whereas ICAM-1, the receptor of major group HRVs actively contributes to viral uncoating, LDLRs are rather considered passive vehicles for cargo delivery to the low-pH environment of endosomes. Since the Tyr-Trp-Thr-Asp β-propeller domain of LDLR has been shown to be involved in the dissociation of bound LDL via intramolecular competition at low pH, we studied whether it also plays a role in HRV infection. Human cell lines deficient in LDLR family proteins are not available. Therefore, we used CHO-ldla7 cells that lack endogenous LDLR. These were stably transfected to express either wild-type (wt) human LDLR or a mutant with a deletion of the β-propeller. When HRV2 was attached to the propeller-negative LDLR, a lower pH was required for conversion to subviral particles than when attached to wt LDLR. This indicates that high-avidity receptor binding maintains the virus in its native conformation. HRV2 internalization directed the mutant LDLR but not wt LDLR to lysosomes, resulting in reduced plasma membrane expression of propeller-negative LDLR. Infection assays using a CHO-adapted HRV2 variant showed a delay in intracellular viral conversion and de novo viral synthesis in cells expressing the truncated LDLR. Our data indicate that the β-propeller attenuates the virus-stabilizing effect of LDLR binding and thereby facilitates RNA release from endosomes, resulting in the enhancement of infection. This is a nice example of a virus exploiting high-avidity multimodule receptor binding with an intrinsic release mechanism.
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Duff, Christopher J., Martin J. Scott, Ian T. Kirby, Sue E. Hutchinson, Steve L. Martin, and Nigel M. Hooper. "Antibody-mediated disruption of the interaction between PCSK9 and the low-density lipoprotein receptor." Biochemical Journal 419, no. 3 (April 14, 2009): 577–84. http://dx.doi.org/10.1042/bj20082407.
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PCSK9 (proprotein convertase subtilisin/kexin type 9) promotes degradation of the LDLR [LDL (low-density lipoprotein) receptor] through an as-yet-undefined mechanism, leading to a reduction in cellular LDLc (LDL-cholesterol) and a concomitant increase in serum LDLc. Central to the function of PCSK9 is a direct protein–protein interaction formed with the LDLR. In the present study, we investigated a strategy to modulate LDL uptake by blocking this interaction using specific antibodies directed against PCSK9. Studies using surface plasmon resonance demonstrated that direct binding of PCSK9 to the LDLR could be abolished with three different anti-PCSK9 antibodies. Two of these antibodies were raised against peptide epitopes in a region of the catalytic domain of PCSK9 that is involved in the interaction with the LDLR. Such antibodies restored LDL uptake in HepG2 cells treated with exogenous PCSK9 and in HepG2 cells engineered to overexpress recombinant PCSK9. This latter observation indicates that antibodies blocking the PCSK9–LDLR interaction can inhibit the action of PCSK9 produced endogenously in a cell-based system. These antibodies also disrupted the higher-affinity interaction between the natural gain-of-function mutant of PCSK9, D374Y, and the LDLR in both the cell-free and cell-based assays. These data indicate that antibodies targeting PCSK9 can reverse the PCSK9-mediated modulation of cell-surface LDLRs.
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Sanguino Otero, Javier, Carmen Rodríguez-Jiménez, Jose Mostaza Prieto, Carlos Rodríguez-Antolín, Ana Carazo Alvarez, Francisco Arrieta Blanco, and Sonia Rodríguez-Nóvoa. "Functional Analysis of 3′UTR Variants at the LDLR and PCSK9 Genes in Patients with Familial Hypercholesterolemia." Human Mutation 2024 (February 8, 2024): 1–15. http://dx.doi.org/10.1155/2024/9964734.
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Familial hypercholesterolemia (FH) is an autosomal dominant disease with an estimated prevalence of 1 in 200-250 individuals. Patients with FH are at increased risk of premature coronary artery disease. Early diagnosis and treatment are essential for improving clinical outcomes. In many cases, however, the genetic diagnosis is not confirmed. At present, routine genetic testing does not analyze the 3′UTR regions of LDLR and PCSK9. However, 3′UTR-single nucleotide variants could be of interest because they can modify the target sequence of miRNAs that regulate the expression of these genes. Our study fully characterizes the 3′UTR regions of LDLR and PCSK9 in 409 patients with a suspected diagnosis of FH using next-generation sequencing. In 30 of the 409 patients, we found 21 variants with an allelic frequency of <1%; 14 of them at 3′UTR-LDLR and 8 at 3′UTR-PCSK9. The variants’ pathogenicity was studied in silico; subsequently, a number of the variants were functionally validated using luciferase reporter assays. LDLR:c.∗653G>C showed a 41% decrease in luciferase expression, while PCSK9:c.∗950C>T showed a 41% increase in PCSK9 expression, results that could explain the hypercholesterolemia phenotype. In summary, the genetic analysis of the 3′UTR regions of LDLR and PCSK9 could improve the genetic diagnosis of FH.
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Rogers, Justin T., and Edwin J. Weeber. "Reelin and apoE actions on signal transduction, synaptic function and memory formation." Neuron Glia Biology 4, no. 3 (August 2008): 259–70. http://dx.doi.org/10.1017/s1740925x09990184.
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Low-density-lipoprotein receptors (LDLRs) are an evolutionarily ancient surface protein family with the ability to activate a diversity of extracellular signals across the cellular membrane in the adult central nervous system (CNS). Their intimate roles in modulating synaptic plasticity and their necessity in hippocampal-dependent learning and memory have only recently come to light. Two known LDLR ligands, specifically apolipoprotein E (apoE) and reelin, have been the most widely investigated in this regard. Most of our understanding of synaptic plasticity comes from investigation of both pre- and postsynaptic alterations. Therefore, it is interesting to note that neurons and glia that do not contribute to the synaptic junction in question can secrete signaling molecules that affect synaptic plasticity. Notably, reelin and apoE have been shown to modulate hippocampal long-term potentiation in general, and affect NMDA receptor and AMPA receptor regulation specifically. Furthermore, these receptors and signaling molecules have significant roles in neuronal degenerative diseases such as Alzheimer's disease. The recent production of recombinant proteins, knockout and transgenic mice for receptors and ligands and the development of human ApoE targeted replacement mice have significantly expanded our understanding of the roles LDLRs and their ligands have in certain disease states and the accompanying initiation of specific signaling pathways. This review describes the role LDLRs, apoE and reelin have in the regulation of hippocampal synaptic plasticity.
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Strøm, Thea Bismo, Katrine Bjune, and Trond P. Leren. "Bone morphogenetic protein 1 cleaves the linker region between ligand-binding repeats 4 and 5 of the LDL receptor and makes the LDL receptor non-functional." Human Molecular Genetics 29, no. 8 (October 10, 2019): 1229–38. http://dx.doi.org/10.1093/hmg/ddz238.
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Abstract The cell-surface low-density lipoprotein receptor (LDLR) internalizes low-density lipoprotein (LDL) by receptor-mediated endocytosis and plays a key role in the regulation of plasma cholesterol levels. The ligand-binding domain of the LDLR contains seven ligand-binding repeats of approximately 40 residues each. Between ligand-binding repeats 4 and 5, there is a 10-residue linker region that is subject to enzymatic cleavage. The cleaved LDLR is unable to bind LDL. In this study, we have screened a series of enzyme inhibitors in order to identify the enzyme that cleaves the linker region. These studies have identified bone morphogenetic protein 1 (BMP1) as being the cleavage enzyme. This conclusion is based upon the use of the specific BMP1 inhibitor UK 383367, silencing of the BMP1 gene by the use of siRNA or CRISPR/Cas9 technology and overexpression of wild-type BMP1 or the loss-of-function mutant E214A-BMP1. We have also shown that the propeptide of BMP1 has to be cleaved at RSRR120↓ by furin-like proprotein convertases for BMP1 to have an activity towards the LDLR. Targeting BMP1 could represent a novel strategy to increase the number of functioning LDLRs in order to lower plasma LDL cholesterol levels. However, a concern by using BMP1 inhibitors as cholesterol-lowering drugs could be the risk of side effects based on the important role of BMP1 in collagen assembly.
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Liou, Je-Wen, Pei-Yi Chen, Wan-Yun Gao, and Jui-Hung Yen. "Natural phytochemicals as small-molecule proprotein convertase subtilisin/kexin type 9 inhibitors." Tzu Chi Medical Journal 36, no. 4 (September 5, 2024): 360–69. http://dx.doi.org/10.4103/tcmj.tcmj_46_24.
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ABSTRACT A decrease in the levels of low-density lipoprotein receptors (LDLRs) leads to the accumulation of LDL cholesterol (LDL-C) in the bloodstream, resulting in hypercholesterolemia and atherosclerotic cardiovascular diseases. Increasing the expression level or inducing the activity of LDLR in hepatocytes can effectively control hypercholesterolemia. Proprotein convertase subtilisin/kexin type 9 (PCSK9) protein, primarily produced in the liver, promotes the degradation of LDLR. Inhibiting the expression and/or function of PCSK9 can increase the levels of LDLR on the surface of hepatocytes and promote LDL-C clearance from the plasma. Thus, targeting PCSK9 represents a new strategy for developing preventive and therapeutic interventions for hypercholesterolemia. Currently, monoclonal antibodies are used as PCSK9 inhibitors in clinical practice. However, the need for oral and affordable anti-PCSK9 medications limits the perspective of choosing PCSK9 inhibitors for clinical usage. Emerging research reports have demonstrated that natural phytochemicals have efficacy in maintaining cholesterol stability and regulating lipid metabolism. Developing novel natural phytochemical PCSK9 inhibitors can serve as a starting point for developing small-molecule drugs to reduce plasma LDL-C levels in patients. In this review, we summarize the current literature on the critical role of PCSK9 in controlling LDLR degradation and hypercholesterolemia, and we discuss the results of studies attempting to develop PCSK9 inhibitors, with an emphasis on the inhibitory effects of natural phytochemicals on PCSK9. Furthermore, we provide insight into the mechanisms of action by which the reported phytochemicals exert their potential PCSK9 inhibitory effects against hypercholesterolemia.
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Vargas-Alarcon, Gilberto, Oscar Perez-Mendez, Julian Ramirez-Bello, Rosalinda Posadas-Sanchez, Hector Gonzalez-Pacheco, Galileo Escobedo, Betzabe Nieto-Lima, Elizabeth Carreon-Torres, and Jose Manuel Fragoso. "The c.*52 A/G and c.*773 A/G Genetic Variants in the UTR′3 of the LDLR Gene Are Associated with the Risk of Acute Coronary Syndrome and Lower Plasma HDL-Cholesterol Concentration." Biomolecules 10, no. 10 (September 29, 2020): 1381. http://dx.doi.org/10.3390/biom10101381.
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Dyslipidemia has a substantial role in the development of acute coronary syndrome (ACS). Low-density lipoprotein receptor (LDLR) plays a critical role in plasma lipoprotein hemostasis, which is involved in the formation of atherosclerotic plaque. This study aimed to evaluate whether LDLR gene polymorphisms are significantly associated with ACS and the plasma lipids profile. Three LDLR gene polymorphisms located in the UTR′3 region (c.*52 A/G, c.*504 A/G, and c.* 773 A/G) were determined using TaqMan genotyping assays in a group of 618 ACS patients and 666 healthy controls. Plasma lipids profile concentrations were determined by enzymatic/colorimetric assays. Under co-dominant and recessive models, the c.*52 A allele of the c.*52 A/G polymorphism was associated with a higher risk of ACS (OR = 2.02, pCCo-dom = 0.033, and OR = 2.00, pCRes = 0.009, respectively). In the same way, under co-dominant and recessive models, the c.*773 G allele of the c.*773 A/G polymorphism was associated with a high risk of ACS (OR = 2.04, pCCo-dom = 0.027, and OR = 2.01, pCRes = 0.007, respectively). The “AAG” haplotype was associated with a high risk of ACS (OR = 1.22, pC = 0.016). The c.*52 AA genotype showed a lower HDL-C concentration than individuals with the GG genotype. In addition, carriers of c.*773 GG genotype carriers had a lower concentration of the high-density lipoprotein-cholesterol (HDL-C) than subjects with the AA genotype. Our data suggest the association of the LDLRc.*773 A/G and LDLR c.*52 A/G polymorphisms with both the risk of developing ACS and with a lower concentration of HDL-C in the study population.
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Suzuki, Yasuhiro, Nobuo Nagai, Kasumi Yamakawa, Yoshinori Muranaka, Kazuya Hokamura, and Kazuo Umemura. "Recombinant Tissue-Type Plasminogen Activator Transiently Enhances Blood–Brain Barrier Permeability During Cerebral Ischemia through Vascular Endothelial Growth Factor-Mediated Endothelial Endocytosis in Mice." Journal of Cerebral Blood Flow & Metabolism 35, no. 12 (July 29, 2015): 2021–31. http://dx.doi.org/10.1038/jcbfm.2015.167.
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Recombinant tissue-type plasminogen activator (rt-PA) modulates cerebrovascular permeability and exacerbates brain injury in ischemic stroke, but its mechanisms remain unclear. We studied the involvement of vascular endothelial growth factor (VEGF)-mediated endocytosis in the increase of blood-brain barrier (BBB) permeability potentiated by rt-PA after ischemic stroke. The rt-PA treatment at 4 hours after middle cerebral artery occlusion induced a transient increase in BBB permeability after ischemic stroke in mice, which was suppressed by antagonists of either low-density lipoprotein receptor families (LDLRs) or VEGF receptor-2 (VEGFR-2). In immortalized bEnd.3 endothelial cells, rt-PA treatment upregulated VEGF expression and VEGFR-2 phosphorylation under ischemic conditions in an LDLR-dependent manner. In addition, rt-PA treatment increased endocytosis and transcellular transport in bEnd.3 monolayers under ischemic conditions, which were suppressed by the inhibition of LDLRs, VEGF, or VEGFR-2. The rt-PA treatment also increased the endocytosis of endothelial cells in the ischemic brain region after stroke in mice. These findings indicate that rt-PA increased BBB permeability via induction of VEGF, which at least partially mediates subsequent increase in endothelial endocytosis. Therefore, inhibition of VEGF induction may have beneficial effects after thrombolytic therapy with rt-PA treatment after stroke.
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Cao, Yunpeng, Haili Wang, Ping Jin, Fei Ma, and Xue Zhou. "Identification and Characterization of the Very-Low-Density Lipoprotein Receptor Gene from Branchiostoma belcheri: Insights into the Origin and Evolution of the Low-Density Lipoprotein Receptor Gene Family." Animals 13, no. 13 (July 4, 2023): 2193. http://dx.doi.org/10.3390/ani13132193.
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Low-density lipoprotein receptors (LDLRs) are a class of cell-surface endocytosis receptors that are mainly involved in cholesterol homeostasis and cellular signal transduction. Very-low-density lipoprotein receptors (VLDLRs), which are members of the LDLR family, have been regarded as multi-function receptors that fulfill diverse physiological functions. However, no VLDLR gene has been identified in protochordates to date. As a representative protochordate species, amphioxi are the best available example of vertebrate ancestors. Identifying and characterizing the VLDLR gene in amphioxi has high importance for exploring the evolutionary process of the LDLR family. With this study, a new amphioxus VLDLR gene (designated AmphiVLDLR) was cloned and characterized using RACE-PCR. The 3217 nt transcript of the AmphiVLDLR had a 2577 nt ORF, and the deduced 858 amino acids were highly conserved within vertebrate VLDLRs according to their primary structure and three-dimensional structure, both of which contained five characteristic domains. In contrast to other vertebrate VLDLRs, which had a conserved genomic structure organization with 19 exons and 18 introns, the AmphiVLDLR had 13 exons and 12 introns. The results of a selective pressure analysis showed that the AmphiVLDLR had numerous positive selection sites. Furthermore, the tissue expression of AmphiVLDLR using RT-qPCR showed that AmphiVLDLR RNA expression levels were highest in the gills and muscles, moderate in the hepatic cecum and gonads, and lowest in the intestines. The results of the evolutionary analysis demonstrated that the AmphiVLDLR gene is a new member of the VLDLR family whose family members have experienced duplications and deletions over the evolutionary process. These results imply that the functions of LDLR family members have also undergone differentiation. In summary, we found a new VLDLR gene homolog (AmphiVLDLR) in amphioxi. Our results provide insight into the function and evolution of the LDLR gene family.
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Sasaki, Minoru, Yu Shimoyama, Yoshitoyo Kodama, and Taichi Ishikawa. "Tryptophanyl tRNA Synthetase from Human Macrophages Infected by Porphyromonas gingivalis Induces a Proinflammatory Response Associated with Atherosclerosis." Pathogens 10, no. 12 (December 20, 2021): 1648. http://dx.doi.org/10.3390/pathogens10121648.
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Porphyromonas gingivalis is the most common microorganism associated with adult periodontal disease, causing inflammation around the subgingival lesion. In this study, we investigated tryptophanyl tRNA synthase (WRS) production by THP-1 cells infected with P. gingivalis. Cytokine production, leukocyte adhesion molecules, and low-density lipoprotein receptor (LDLR) expressions in cultured cells were examined. WRS was detected in THP-1 cell culture supernatants stimulated with P. gingivalis from 1 to 24 h, and apparent production was observed after 4 h. No change in WRS mRNA expression was observed from 1 to 6 h in THP-1 cells, whereas its expression was significantly increased 12 h after stimulation with P. gingivalis. Lactate dehydrogenase (LDH) activity was observed from 4 to 24 h. The TNF-α, IL-6, IL-8, and CXCL2 levels of THP-1 cells were upregulated after treatment with recombinant WRS (rWRS) and were significantly reduced when THP-1 cells were treated with C29. The MCP-1, ICAM-1, and VCAM-1 levels in human umbilical vein endothelial cells were upregulated following treatment with rWRS, and TAK242 suppressed these effects. Additionally, unmodified LDLR, macrophage scavenger receptor A, and lectin-like oxidized LDLRs were upregulated in THP-1 cells treated with rWRS. These results suggest that WRS from macrophages infected with P. gingivalis is associated with atherosclerosis.
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Ye, Huadan, Qianlei Zhao, Yi Huang, Lingyan Wang, Haibo Liu, Chunming Wang, Dongjun Dai, Leiting Xu, Meng Ye, and Shiwei Duan. "Meta-Analysis of Low Density Lipoprotein Receptor (LDLR) rs2228671 Polymorphism and Coronary Heart Disease." BioMed Research International 2014 (2014): 1–6. http://dx.doi.org/10.1155/2014/564940.
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Low density lipoprotein receptor (LDLR) can regulate cholesterol metabolism by removing the excess low density lipoprotein cholesterol (LDL-C) in blood. Since cholesterol metabolism is often disrupted in coronary heart disease (CHD),LDLRas a candidate gene of CHD has been intensively studied. The goal of our study is to evaluate the overall contribution ofLDLRrs2228671 polymorphism to the risk of CHD by combining the genotyping data from multiple case-control studies. Our meta-analysis is involved with 8 case-control studies among 7588 cases and 9711 controls to test the association betweenLDLRrs2228671 polymorphism and CHD. In addition, we performed a case-control study ofLDLRrs2228671 polymorphism with the risk of CHD in Chinese population. Our meta-analysis showed that rs2228671-T allele was significantly associated with a reduced risk of CHD (P=0.0005, odds ratio (OR) = 0.83, and 95% confidence interval (95% CI) = 0.75–0.92). However, rs2228671-T allele frequency was rare (1%) and was not associated with CHD in Han Chinese (P=0.49), suggesting an ethnic difference ofLDLRrs2228671 polymorphism. Meta-analysis has established rs2228671 as a protective factor of CHD in Europeans. The lack of association in Chinese reflects an ethnic difference of this genetic variant between Chinese and European populations.
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Mayne, Janice, Thilina Dewpura, Angela Raymond, Lise Bernier, Marion Cousins, Teik Chye Ooi, Jean Davignon, Nabil G. Seidah, Majambu Mbikay, and Michel Chrétien. "Novel Loss-of-Function PCSK9 Variant Is Associated with Low Plasma LDL Cholesterol in a French-Canadian Family and with Impaired Processing and Secretion in Cell Culture." Clinical Chemistry 57, no. 10 (October 1, 2011): 1415–23. http://dx.doi.org/10.1373/clinchem.2011.165191.
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BACKGROUND PCSK9 (proprotein convertase subtilisin/kexin type 9) is a polymorphic gene whose protein product regulates plasma LDL cholesterol (LDLC) concentrations by shuttling liver LDL receptors (LDLRs) for degradation. PCSK9 variants that cause a gain or loss of PCSK9 function are associated with hyper- or hypocholesterolemia, which increases or reduces the risk of cardiovascular disease, respectively. We studied the clinical and molecular characteristics of a novel PCSK9 loss-of-function sequence variant in a white French-Canadian family. METHODS In vivo plasma and ex vivo secreted PCSK9 concentrations were measured with a commercial ELISA. We sequenced the PCSK9 exons for 15 members of a family, the proband of which exhibited very low plasma PCSK9 and LDLC concentrations. We then conducted a structure/function analysis of the novel PCSK9 variant in cell culture to identify its phenotypic basis. RESULTS We identified a PCSK9 sequence variant in the French-Canadian family that produced the PCSK9 Q152H substitution. Family members carrying this variant had mean decreases in circulating PCSK9 and LDLC concentrations of 79% and 48%, respectively, compared with unrelated noncarriers (n=210). In cell culture, the proPCSK9-Q152H variant did not undergo efficient autocatalytic cleavage and was not secreted. Cells transiently transfected with PCSK9-Q152H cDNA had LDLR concentrations that were significantly higher than those of cells overproducing wild-type PCSK9 (PCSK9-WT). Cotransfection of PCSK9-Q152H and PCSK9-WT cDNAs produced a 78% decrease in the secreted PCSK9-WT protein compared with control cells. CONCLUSIONS Collectively, our results demonstrate that the PCSK9-Q152H variant markedly lowers plasma PCSK9 and LDLC concentrations in heterozygous carriers via decreased autocatalytic processing and secretion, and hence, inactivity on the LDLR.
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Ali, Akhtar, Ros Whittall, Masroor Ellahi Babar, Tanveer Hussain, and Steve E. Humphries. "Genetics of LDLR Gene in Pakistani Hypercholesterolemia Families." International Journal of Pharma Medicine and Biological Sciences 8, no. 4 (October 2019): 143–46. http://dx.doi.org/10.18178/ijpmbs.8.4.143-146.
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Silvestri, Laura, Flavia Guillem, Alessia Pagani, Antonella Nai, Claire Oudin, Muriel Silva, Fabienne Toutain, et al. "Molecular mechanisms of the defective hepcidin inhibition in TMPRSS6 mutations associated with iron-refractory iron deficiency anemia." Blood 113, no. 22 (May 28, 2009): 5605–8. http://dx.doi.org/10.1182/blood-2008-12-195594.
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Matriptase-2 is a transmembrane serine protease that negatively regulates hepcidin expression by cleaving membrane-bound hemojuvelin. Matriptase-2 has a complex ectodomain, including a C-terminal serine protease domain and its activation requires an autocatalytic cleavage. Matriptase-2 mutations have been reported in several patients with iron-refractory iron deficiency anemia. Here we describe a patient with 2 missense mutations in the second class A low-density lipoprotein receptor (LDLRA) domain. Functional studies of these 2 mutations and of a previously reported mutation in the second C1r/C1s, urchin embryonic growth factor and bone morphogenetic protein 1 (CUB) domain were performed. Transfection of mutant cDNAs showed that membrane targeting of the 2 LDLRA mutants was impaired, with Golgi retention of the variants. The activating cleavage was absent for the LDLRA mutants and reduced for the CUB mutant. All 3 mutated proteins were still able to physically interact with hemojuvelin but only partially repressed hepcidin expression compared with wild-type matriptase-2. Our results underline the importance of LDLRA and CUB domains of matriptase-2.
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Larrea-Sebal, Asier, Asier Benito-Vicente, José A. Fernandez-Higuero, Shifa Jebari-Benslaiman, Unai Galicia-Garcia, Kepa B. Uribe, Ana Cenarro, et al. "MLb-LDLr." JACC: Basic to Translational Science 6, no. 11 (November 2021): 815–27. http://dx.doi.org/10.1016/j.jacbts.2021.08.009.
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Bashir, Nabil. "Effects of Hinc II Polymorphism in the LDL Receptor Gene on Serum Lipid Levels of Jordanian Individuals with High Risk for Coronary Heart Disease." American Journal of Laboratory Medicine 9, no. 5 (December 16, 2024): 58–63. https://doi.org/10.11648/j.ajlm.20240905.12.
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Coronary heart disease (CHD) has presented high prevalence in the Jordanian population. Nevertheless, studies of genetic risk factors for CHD in our country are insufficiently carried out. We are intended to investigated the effects of Hinc II (exon 12) polymorphisms at the low-density lipoprotein receptor (LDLR) gene on circulating lipids of 150 individuals with high risk for CHD (HRG) and 150 controls (C). Genomic DNA was extracted from white blood cells and amplified by polymerase chain reaction (PCR) and digested with HincII Restriction enzyme. LDL, TC (total cholesterol), TG (triglycerides), and HDL (high density lipoproteins) levels were measured in all subjects. RFLP (restriction fragment length polymorphism) analysis was conducted to identify genotype of LDLR gene in (HRG) and 150 controls (C). The results showed a significant correlation existed between this RFLP locus and (HRG), X2=10.6, P<0.05; H<sup>+</sup> allele frequency: X2=7.88, P<0.05., H<sup>-</sup> allele frequency: X2=7.88, P<0.05. Genotypes H<sup>+</sup>H<sup>+</sup> and H<sup>+</sup>H<sup>- </sup>in high risk group are significantly associated with high levels of LDL, TC, TG, P<0.05 and with low level of HDL P<0.05., while H<sup>-</sup>H<sup>-</sup> is associated with normal values of serum lipids P<0.05. It is inferred that H<sup>+</sup> allele might be associated with high blood cholesterol level, and the H<sup>-</sup> allele with normal level. This study suggests that the differences in LDLRG genotypes might affect the phenotype of lipid metabolism.
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Pirmoradi, Leila, Nayer Seyfizadeh, Saeid Ghavami, Amir A. Zeki, and Shahla Shojaei. "Targeting cholesterol metabolism in glioblastoma: a new therapeutic approach in cancer therapy." Journal of Investigative Medicine 67, no. 4 (February 14, 2019): 715–19. http://dx.doi.org/10.1136/jim-2018-000962.
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Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor known with a poor survival rate despite current advances in the field of cancer. Additional research into the pathophysiology of GBM is urgently needed given the devastating nature of this disease. Recent studies have revealed the unique cellular physiology of GBM cells as compared with healthy astrocytes. Intriguingly, GBM cells are incapable of de novo cholesterol synthesis via the mevalonate pathway. Thus, the survival of GBM cells depends on cholesterol uptake via low-density lipoprotein receptors (LDLRs) in the form of apolipoprotein-E-containing lipoproteins and ATP-binding cassette transporter A1 (ABCA1) that efflux surplus cholesterol out of cells. Liver X receptors regulate intracellular cholesterol levels in neurons and healthy astrocytes through changes in the expression of LDLR and ABCA1 in response to cholesterol and its derivatives. In GBM cells, due to the dysregulation of this surveillance pathway, there is an accumulation of intracellular cholesterol. Furthermore, intracellular cholesterol regulates temozolomide-induced cell death in glioblastoma cells via accumulation and activation of death receptor 5 in plasma membrane lipid rafts. The mevalonate pathway and autophagy flux are also fundamentally related with implications for cell health and death. Thus, via cholesterol metabolism, the mevalonate pathway may be a crucial player in the pathogenesis and treatment of GBM where our current understanding is still lacking. Targeting cholesterol metabolism in GBM may hold promise as a novel adjunctive clinical therapy for this devastating cancer.
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Bovenschen, Niels, Koen Mertens, Lihui Hu, Louis M. Havekes, and Bart J. M. van Vlijmen. "LDL receptor cooperates with LDL receptor–related protein in regulating plasma levels of coagulation factor VIII in vivo." Blood 106, no. 3 (August 1, 2005): 906–12. http://dx.doi.org/10.1182/blood-2004-11-4230.
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Abstract Low-density lipoprotein (LDL) receptor (LDLR) and LDLR-related protein (LRP) are members of the LDLR family of endocytic receptors. LRP recognizes a wide spectrum of structurally and functionally unrelated ligands, including coagulation factor VIII (FVIII). In contrast, the ligand specificity of LDLR is restricted to apolipoproteins E and B-100. Ligand binding to the LDLR family is inhibited by receptor-associated protein (RAP). We have previously reported that, apart from LRP, other RAP-sensitive mechanisms contribute to the regulation of FVIII in vivo. In the present study, we showed that the extracellular ligand-binding domain of LDLR interacts with FVIII in vitro and that binding was inhibited by RAP. The physiologic relevance of the FVIII–LDLR interaction was addressed using mouse models of LDLR or hepatic LRP deficiency. In the absence of hepatic LRP, LDLR played a dominant role in the regulation and clearance of FVIII in vivo. Furthermore, FVIII clearance was accelerated after adenovirus-mediated gene transfer of LDLR. The role of LDLR in FVIII catabolism was not secondary to increased plasma lipoproteins or to changes in lipoprotein profiles. We propose that LDLR acts in concert with LRP in regulating plasma levels of FVIII in vivo. This represents a previously unrecognized link between LDLR and hemostasis.
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Kang, Yuan-Lin, John Yochem, Leslie Bell, Erika B. Sorensen, Lihsia Chen, and Sean D. Conner. "Caenorhabditis elegans reveals a FxNPxY-independent low-density lipoprotein receptor internalization mechanism mediated by epsin1." Molecular Biology of the Cell 24, no. 3 (February 2013): 308–18. http://dx.doi.org/10.1091/mbc.e12-02-0163.
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Low-density lipoprotein receptor (LDLR) internalization clears cholesterol-laden LDL particles from circulation in humans. Defects in clathrin-dependent LDLR endocytosis promote elevated serum cholesterol levels and can lead to atherosclerosis. However, our understanding of the mechanisms that control LDLR uptake remains incomplete. To identify factors critical to LDLR uptake, we pursued a genome-wide RNA interference screen using Caenorhabditis elegans LRP-1/megalin as a model for LDLR transport. In doing so, we discovered an unanticipated requirement for the clathrin-binding endocytic adaptor epsin1 in LDLR endocytosis. Epsin1 depletion reduced LDLR internalization rates in mammalian cells, similar to the reduction observed following clathrin depletion. Genetic and biochemical analyses of epsin in C. elegans and mammalian cells uncovered a requirement for the ubiquitin-interaction motif (UIM) as critical for receptor transport. As the epsin UIM promotes the internalization of some ubiquitinated receptors, we predicted LDLR ubiquitination as necessary for endocytosis. However, engineered ubiquitination-impaired LDLR mutants showed modest internalization defects that were further enhanced with epsin1 depletion, demonstrating epsin1-mediated LDLR endocytosis is independent of receptor ubiquitination. Finally, we provide evidence that epsin1-mediated LDLR uptake occurs independently of either of the two documented internalization motifs (FxNPxY or HIC) encoded within the LDLR cytoplasmic tail, indicating an additional internalization mechanism for LDLR.
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Huang, Yong, Ke Ning, Wen-Wen Li, Ge Lin, Cui-Lan Hou, Ming-Jie Wang, and Yi-Chun Zhu. "Hydrogen sulfide accumulates LDL receptor precursor via downregulating PCSK9 in HepG2 cells." American Journal of Physiology-Cell Physiology 319, no. 6 (December 1, 2020): C1082—C1096. http://dx.doi.org/10.1152/ajpcell.00244.2019.
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Endogenous hydrogen sulfide (H2S) affects cholesterol homeostasis and liver X receptor α (LXRα) expression. However, whether low-density lipoprotein (LDL) receptor (LDLR), a key player in cholesterol homeostasis, is regulated by exogenous H2S through LXRα signaling has not been determined. We investigated the effects of sodium hydrosulfide (NaHS, H2S donor) on LDLR expression in the presence or absence of LXR agonists, T0901317 or GW3965 in HepG2 cells. We found that H2S strongly accumulated LDLR precursor in the presence of T0901317. Hence, LDLR transcription and the genes involved in LDLR precursor maturation and degradation were studied. T0901317 increased the LDLR mRNA level, whereas H2S did not affect LDLR transcription. H2S had no significant effect on the expression of LXRα and inducible degrader of LDLR (IDOL). H2S and T0901317 altered mRNA levels of several enzymes for N- and O-glycosylation and endoplasmic reticulum (ER) chaperones assisting LDLR maturation, but did not affect their protein levels. H2S decreased proprotein convertase subtilisin/kexin type 9 (PCSK9) protein levels and its mRNA level elevated by T0901317. T0901317 with PCSK9 siRNA also accumulated LDLR precursor as did T0901317 with H2S. High glucose increased PCSK9 protein levels and attenuated LDLR precursor accumulation induced by T0901317 with H2S. Taken together, H2S accumulates LDLR precursor by downregulating PCSK9 expression but not through the LXRα-IDOL pathway, LDLR transcriptional activation, or dysfunction of glycosylation enzymes and ER chaperones. These results also indicate that PCSK9 plays an important role in LDLR maturation in addition to its well-known effect on the degradation of LDLR mature form.
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Guo, Tao, Liang Zhang, Dong Cheng, Tao Liu, Liguo An, Wei-Ping Li, and Cong Zhang. "Low-density lipoprotein receptor affects the fertility of female mice." Reproduction, Fertility and Development 27, no. 8 (2015): 1222. http://dx.doi.org/10.1071/rd13436.
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Low-density lipoprotein receptor (LDLR) has been demonstrated to play a central role in lipoprotein metabolism, with Ldlr-deficient (Ldlr–/–) mice developing severe dyslipidemia. In the present study we investigated whether Ldlr knockout could harm female reproduction and explored the mechanisms involved. The results indicate that although the number of litters born to Ldlr–/– mice did not differ significantly from that born to controls, the number of pups per litter was significantly lower in the former group. Interestingly, although Ldlr–/– mice were obese, the weight of their ovaries was lower than that in control mice. Serum cholesterol levels was significantly higher in Ldlr–/– mice than in their wild-type counterparts. In contrast, there were significant decreases in cholesterol, triglyceride and total lipid levels in ovaries of Ldlr–/– mice. Both ovarian lipid deposition, as detected by Oil red O staining, and lipid droplets, as evaluated by transmission electron microscopy, supported decreased lipid levels in ovaries from Ldlr–/– mice. In addition, Ldlr–/– mice had fewer ovarian follicles, more atretic follicles, lower oestrogen levels and spent significantly less time in oestrus than did the controls. Superovulation assays indicated immature Ldlr–/– mice ovulated fewer ova than controls. These results indicate that lack of Ldlr results in dyslipidaemia and poor fertility.
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Ngai, Ying Fai, Whitney L. Quong, Melissa B. Glier, Maria M. Glavas, Sandra L. Babich, Sheila M. Innis, Timothy J. Kieffer, and William T. Gibson. "Ldlr−/− Mice Display Decreased Susceptibility to Western-Type Diet-Induced Obesity Due to Increased Thermogenesis." Endocrinology 151, no. 11 (September 29, 2010): 5226–36. http://dx.doi.org/10.1210/en.2010-0496.
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The low-density lipoprotein receptor (Ldlr) is a key molecule involved with lipid clearance. The Ldlr−/− mouse has been used extensively as a model for studying atherosclerosis. This study sought to characterize the energy balance phenotype of Ldlr−/− mice with respect to weight gain, body composition, energy expenditure (EE), glucose homeostasis, and leptin sensitivity. Adult Ldlr−/− mice and Ldlr+/+ controls on a C57Bl/6J background were fed either a chow or a high-fat, high-sucrose Western-type diet (WTD) for eight wk. Physiological studies of food intake, EE, activity, insulin sensitivity, and leptin responsiveness were performed. The effect of these diet interventions on circulating leptin and on leptin gene expression was also examined. On the chow diet, Ldlr−/− mice had lower EE and higher activity levels relative to controls. On the WTD, Ldlr−/− mice gained less weight relative to Ldlr+/+ mice, specifically gaining less fat mass. Increased thermogenesis in Ldlr−/− mice fed the WTD was detected. Additionally, leptin responsiveness was blunted in chow-fed Ldlr−/− mice, suggesting a novel role for the Ldlr pathway that extends to leptin’s regulation of energy balance. In addition to its known role in lipid transport, these results demonstrate the importance of the Ldlr in energy homeostasis and suggest a direct physiological link between altered lipid transport and energy balance.
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Gurzeler, Erika, Anna-Kaisa Ruotsalainen, Anssi Laine, Teemu Valkama, Sanna Kettunen, Markku Laakso, and Seppo Ylä-Herttuala. "SUR1-E1506K mutation impairs glucose tolerance and promotes vulnerable atherosclerotic plaque phenotype in hypercholesterolemic mice." PLOS ONE 16, no. 11 (November 12, 2021): e0258408. http://dx.doi.org/10.1371/journal.pone.0258408.
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Background and aims Diabetes is a major risk factor of atherosclerosis and its complications. The loss-of-function mutation E1506K in the sulfonylurea receptor 1 (SUR1-E1506K) induces hyperinsulinemia in infancy, leading to impaired glucose tolerance and increased risk of type 2 diabetes. In this study, we investigate the effect of SUR1-E1506K mutation on atherogenesis in hypercholesterolemic LDLR-/- mice. Methods SUR1-E1506K mutated mice were cross-bred with LDLR-/- mice (SUR1Δ/LDLR-/-), 6 months old mice were fed a western-diet (WD) for 6 months to induce advanced atherosclerotic plaques. At the age of 12 months, atherosclerosis and plaque morphology were analyzed and mRNA gene expression were measured from aortic sections and macrophages. Glucose metabolism was characterized before and after WD. Results were compared to age-matched LDLR-/- mice. Results Advanced atherosclerotic plaques did not differ in size between the two strains. However, in SUR1Δ/LDLR-/- mice, plaque necrotic area was increased and smooth muscle cell number was reduced, resulting in higher plaque vulnerability index in SUR1Δ/LDLR-/- mice compared to LDLR-/- mice. SUR1Δ/LDLR-/- mice exhibited impaired glucose tolerance and elevated fasting glucose after WD. The positive staining area of IL-1β and NLRP3 inflammasome were increased in aortic sections in SUR1Δ/LDLR-/- mice compared to LDLR-/- mice, and IL-18 plasma level was elevated in SUR1Δ/LDLR-/- mice. Finally, the mRNA expression of IL-1β and IL-18 were increased in SUR1Δ/LDLR-/- bone marrow derived macrophages in comparison to LDLR-/- macrophages in response to LPS. Conclusions SUR1-E1506K mutation impairs glucose tolerance and increases arterial inflammation, which promotes a vulnerable atherosclerotic plaque phenotype in LDLR-/- mice.
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JONG, Miek C., Ko WILLEMS Van DIJK, Vivian E. H. DAHLMANS, Hans Van Der BOOM, Kunisha KOBAYASHI, Kazuhito OKA, Gerard SIEST, Lawrence CHAN, Marten H. HOFKER, and Louis M. HAVEKES. "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." Biochemical Journal 338, no. 2 (February 22, 1999): 281–87. http://dx.doi.org/10.1042/bj3380281.
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We have shown previously that human apolipoprotein (apo)C1 transgenic mice exhibit hyperlipidaemia, due primarily to an impaired clearance of very-low-density lipoprotein (VLDL) particles from the circulation. In the absence of at least the low-density-lipoprotein receptor (LDLR), it was shown that APOC1 overexpression in transgenic mice inhibited the hepatic uptake of VLDL via the LDLR-related protein. In the present study, we have now examined the effect of apoC1 on the binding of lipoproteins to both the VLDL receptor (VLDLR) and the LDLR. The binding specificity of the VLDLR and LDLR for apoC1-enriched lipoprotein particles was examined in vivo through adenovirus-mediated gene transfer of the VLDLR and the LDLR [giving rise to adenovirus-containing (Ad)-VLDLR and Ad-LDLR respectively] in APOC1 transgenic mice, LDLR-deficient (LDLR-/-) mice and wild-type mice. Remarkably, Ad-VLDLR treatment did not reduce hyperlipidaemia in transgenic mice overexpressing human APOC1, irrespective of both the level of transgenic expression and the presence of the LDLR, whereas Ad-VLDLR treatment did reverse hyperlipidaemia in LDLR-/- and wild-type mice. On the other hand, Ad-LDLR treatment strongly decreased plasma lipid levels in these APOC1 transgenic mice. These results suggest that apoC1 inhibits the clearance of lipoprotein particles via the VLDLR, but not via the LDLR. This hypothesis is corroborated by in vitro binding studies. Chinese hamster ovary (CHO) cells expressing the VLDLR (CHO-VLDLR) or LDLR (CHO-LDLR) bound less APOC1 transgenic VLDL than wild-type VLDL. Intriguingly, however, enrichment with apoE enhanced dose-dependently the binding of wild-type VLDL to CHO-VLDLR cells (up to 5-fold), whereas apoE did not enhance the binding of APOC1 transgenic VLDL to these cells. In contrast, for binding to CHO-LDLR cells, both wild-type and APOC1 transgenic VLDL were stimulated upon enrichment with apoE. From these studies, we conclude that apoC1 specifically inhibits the apoE-mediated binding of triacylglycerol-rich lipoprotein particles to the VLDLR, whereas apoC1-enriched lipoproteins can still bind to the LDLR. The variability in specificity of these lipoprotein receptors for apoC1-containing lipoprotein particles provides further evidence for a regulatory role of apoC1 in the delivery of lipoprotein constituents to different tissues on which these receptors are located.
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Eslami, Seyyed Majid, Shekoufeh Nikfar, Maryam Ghasemi, and Mohammad Abdollahi. "Does Evolocumab, as a PCSK9 Inhibitor, Ameliorate the Lipid Profile in Familial Hypercholesterolemia Patients? A Meta-Analysis of Randomized Controlled Trials." Journal of Pharmacy & Pharmaceutical Sciences 20 (April 11, 2017): 81. http://dx.doi.org/10.18433/j36c8n.
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Proprotein convertase subtilisin-kexin type 9 (PCSK9) is a member of regulatory serine proteases which is mostly expressed in liver. In the physiological condition, LDL-C binds to LDL receptors (LDLRs) and via endocytosis, LDLRs are degraded. PCSK9 binds to the epidermal growth factor-like repeat A (EGFA) domain of extracellular LDLRs, and then physiological recycling of LDLRs from surface of liver is cancelled, resulting in elevation of circulating LDL-C in plasma. To evaluate whether evolucomab, as PCSK9 inhibitor monoclonal antibody, ameliorates lipid profile in familial hypercholesterolemia (FH) patients, this meta-analysis has been conducted. PubMed, Web of Science (ISI) and Scopus databases were searched for studies which had investigated the efficacy of evolucomab. Types of outcome investigated were percentage changes from baseline of the lipid profile. Our meta-analysis shows that evolucomab at the dosage of 420 mg monthly could decrease LDL-C by 54.71%, TC by 35.08%, VLDL-C by 28.37 %, ratio of TC to HDL-C by 39.14 %, triglycerides by 12.11 %, and increased HDL-C by 6.06% from baseline compared to placebo at the end of study in FH patients. Our findings indicate that evolocumab could be a hopeful agent for challenging patients, such as statin intolerance or patients who fail to attain the target goal of LDL-C despite consumption of maximum doses of statins. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
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Mertens, Koen, Niels Bovenschen, Louis M. Havekes, and Bart J. M. van Vlijmen. "Role of Low Density Lipoprotein Receptor in the Clearance of Coagulation Factor VIII In Vivo." Blood 104, no. 11 (November 16, 2004): 1925. http://dx.doi.org/10.1182/blood.v104.11.1925.1925.
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Abstract Low Density Lipoprotein Receptor (LDLR) is the archetype of the family of endocytic receptors that also includes Low-density lipoprotein Receptor-related Protein (LRP), Megalin, and Very Low Density Lipoprotein Receptor (VLDLR). While most of these receptors bind a variety of ligands, LDLR has restricted specifity. Its known ligands are apolipoprotein E (apoE) and apolipoprotein B100 (apoB100). Ligand binding to the LDL-receptor family is inhibited by the Receptor-Associated Protein (RAP). We have previously reported that RAP overexpression elevates plasma levels of factor VIII (FVIII) in both normal mice and mice with hepatic LRP deficiency [Bovenschen et al. (2003) Blood 101, 3933–3939]. This implies that LRP, but also another RAP-sensitive mechanism contributes to the regulation of FVIII in vivo. This study addresses the question whether LDLR, despite its restricted ligand specificity, binds FVIII and contributes to its clearance. In vitro binding was studied using a recombinant LDLR fragment spanning the extracellular domain of complement-type repeats 1–7. The purified fragment efficiently bound to immobilized ApoE and apoB-100 containing LDL. The immobilized LDLR fragment also bound human FVIII, with half-maximal binding at 156 nM FVIII, and binding was inhibited by RAP. Human von Willebrand Factor (VWF) or non-activated factor IX did not bind to the LDLR fragment. The relevance of the FVIII-LDLR interaction was assessed in vivo employing LDLR−/− mice, cre/loxP-mediated conditional LRP-deficient mice (LRP−), and mice with the combined deficiency. Plasma FVIII levels of controls, LDLR−/− and LRP− mice were 1.1, 0.9 and 1.8 U/ml, respectively. This suggests that LRP, but not LDLR regulates FVIII in plasma. Surprisingly, however, mice that combined LDLR deficiency with hepatic LRP deficiency displayed much higher FVIII levels (median value 4.6 U/ml) than mice lacking LRP alone. This suggests that LDLR does have the potential of regulating FVIII levels. LDLR−/− LRP− mice further displayed elevated levels of VWF (median value 3.3 U/ml), but not of factor V or factor IX. The possibility was considered that FVIII levels were elevated secondary to the profound changes in lipoprotein profiles. To this end, we also examined ApoE deficient mice, which have reduced LDL, and mice that overexpress ApoC1, which is associated with elevated levels of cholesterol- and triglyceride VLDL. ApoE−/− LDLR−/−LRP− mice had a median FVIII level of 4.2 U/ml, which is close to that of LDLR−/−LRP− mice. Mice that overexpressed human ApoC1 had elevated levels of cholesterol and triglycerides, but 0.5 U/ml FVIII. This demonstrates that elevated FVIII levels were independent of lipoprotein levels. The role of LDLR and LRP in FVIII clearance were further studied by analyzing the pharmacokinetics of human FVIII. In normal mice the Mean Residence Time (MRT) was 160 min [68% confidence intervals (CI) 117–218 min]. MRT was 200 [CI 154–259] min in LDLR−/− mice, and 263 [CI 206–336] min in LRP− mice. This confirms the previously described role of LRP in FVIII clearance. Strikingly, in LDLR−/−LRP− mice the MRT of FVIII was 760 [691–826] min, which is approximately 5-fold longer than in control mice. These data demonstrate that LRP and LDLR act in concert in regulating FVIII levels in plasma. In the absence of LDLR, LRP maintains normal FVIII levels, while hepatic LRP deficiency is largely compensated by LDLR. This regulatory role of LDLR represents a novel link between LDLR and the hemostatic system.
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Srivastava, Rai Ajit K. "A Review of Progress on Targeting LDL Receptor-Dependent and -Independent Pathways for the Treatment of Hypercholesterolemia, a Major Risk Factor of ASCVD." Cells 12, no. 12 (June 16, 2023): 1648. http://dx.doi.org/10.3390/cells12121648.
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Since the discovery of the LDL receptor in 1973 by Brown and Goldstein as a causative protein in hypercholesterolemia, tremendous amounts of effort have gone into finding ways to manage high LDL cholesterol in familial hypercholesterolemic (HoFH and HeFH) individuals with loss-of-function mutations in the LDL receptor (LDLR) gene. Statins proved to be the first blockbuster drug, helping both HoFH and HeFH individuals by inhibiting the cholesterol synthesis pathway rate-limiting enzyme HMG-CoA reductase and inducing the LDL receptor. However, statins could not achieve the therapeutic goal of LDL. Other therapies targeting LDLR include PCSK9, which lowers LDLR by promoting LDLR degradation. Inducible degrader of LDLR (IDOL) also controls the LDLR protein, but an IDOL-based therapy is yet to be developed. Among the LDLR-independent pathways, such as angiopoietin-like 3 (ANGPTL3), apolipoprotein (apo) B, apoC-III and CETP, only ANGPTL3 offers the advantage of treating both HoFH and HeFH patients and showing relatively better preclinical and clinical efficacy in animal models and hypercholesterolemic individuals, respectively. While loss-of-LDLR-function mutations have been known for decades, gain-of-LDLR-function mutations have recently been identified in some individuals. The new information on gain of LDLR function, together with CRISPR-Cas9 genome/base editing technology to target LDLR and ANGPTL3, offers promise to HoFH and HeFH individuals who are at a higher risk of developing atherosclerotic cardiovascular disease (ASCVD).
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Dandan, Mohamad, Julia Han, Sabrina Mann, Rachael Kim, Hussein Mohammed, Edna Nyangau, and Marc Hellerstein. "Turnover Rates of the Low-Density Lipoprotein Receptor and PCSK9: Added Dimension to the Cholesterol Homeostasis Model." Arteriosclerosis, Thrombosis, and Vascular Biology 41, no. 12 (December 2021): 2866–76. http://dx.doi.org/10.1161/atvbaha.121.316764.
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Objective: We measured the turnover rates of the LDLR (low-density lipoprotein receptor) and PCSK9 (proprotein convertase subtilisin/kexin type 9) in mice by metabolic labeling with heavy water and mass spectrometry. Approach and Results: In liver of mice fed high-cholesterol diets, LDLR mRNA levels and synthesis rates were markedly lower with complete suppression of cholesterol synthesis and higher cholesterol content, consistent with the Brown-Goldstein model of tissue cholesterol homeostasis. We observed markedly lower PCSK9 mRNA levels and synthesis rates in liver and lower concentrations and synthesis rates in plasma. Hepatic LDLR half-life (t½) was prolonged, consistent with an effect of reduced PCSK9, and resulted in no reduction in hepatic LDLR content despite reduced mRNA levels and LDLR synthesis rates. These changes in PCSK9 synthesis complement and expand the well-established model of tissue cholesterol homeostasis in mouse liver, in that reduced synthesis and levels of PCSK9 counterbalance lower LDLR synthesis by promoting less LDLR catabolism, thereby maintaining uptake of LDL cholesterol into liver despite high intracellular cholesterol concentrations. Conclusions: Lower hepatic synthesis and secretion of PCSK9, an SREBP2 (sterol response element binding protein) target gene, results in longer hepatic LDLR t½ in response to cholesterol feeding in mice in the face of high intracellular cholesterol content. PCSK9 modulation opposes the canonical lowering of LDLR mRNA and synthesis by cholesterol surplus and preserves LDLR levels. The physiological and therapeutic implications of these opposing control mechanisms over liver LDLR are of interest and may reflect subservience of hepatic cholesterol homeostasis to whole body cholesterol needs.
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Chang, Wei-Chun, Hsiao-Ching Wang, Wei-Chung Cheng, Juan-Cheng Yang, Wei-Min Chung, Yen-Pin Ho, Lumin Chen, Yao-Ching Hung, and Wen-Lung Ma. "LDLR-mediated lipidome–transcriptome reprogramming in cisplatin insensitivity." Endocrine-Related Cancer 27, no. 2 (February 2020): 81–95. http://dx.doi.org/10.1530/erc-19-0095.
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Platinum-based therapy remains the cornerstone for cancer therapy; however, its efficacy varies. The role of lipoprotein receptor-mediated lipid entry for cancer development has been reported. Yet, the roles and mechanism of the low-density lipoprotein receptor (LDLR) in chemo-sensitivities are unknown. In the current report, we used epithelial ovarian cancer (EOC), composed of various cellularities, to study this issue. Using public cDNA microarray database and single cohort study, LDLR expressions were positively associated with epithelial ovarian carcinomas (EOCs) platinum-based chemotherapy patients’ disease prognosis. In vitro and in vivo add-in/silencing LDLR was introduced to determine cisplatin sensitivity and cancer growth. Results revealed that knocked-down LDLR could sensitize while overexpressed LDLR could insensitize EOC cells to the cytotoxic effects of cisplatin. Moreover, the trans-omics approaches depicted an LDLR→LPC (Lyso-phosphatidylcholine)→FAM83B (phospholipase-related)→FGFRs (cisplatin sensitivity and phospholipase-related) regulatory axis. Finally, the manipulation of LDLR expression in EOC cells was found to determine the efficacy of cisplatin therapy in terms of tumor suppression. In conclusion, the LDLR→LPC→FAM83B→FGFRs axis is an example of tumor macroenvironmental regulation of therapy outcomes. Relatedly, LDLR expression could serve as a biomarker of chemotherapy sensitivity in EOCs. Significance: this study describes the role of LDLR in the development of insensitivity to platinum-based chemotherapy in epithelial ovarian cancer. The lipidome (e.g., LPC) and transcriptome (e.g., FAM38B) interactions revealed using trans-omics approaches an LDLR→LPC→FAM83B→FGFRs regulatory axis in cancer cells, in an animal model, and in patients.
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Al-Allaf, Faisal A., Zainularifeen Abduljaleel, Mohiuddin M. Taher, Ahmed A. H. Abdellatif, Mohammad Athar, Neda M. Bogari, Mohammed N. Al-Ahdal, et al. "Molecular Dynamics Simulation Reveals Exposed Residues in the Ligand-Binding Domain of the Low-Density Lipoprotein Receptor that Interacts with Vesicular Stomatitis Virus-G Envelope." Viruses 11, no. 11 (November 15, 2019): 1063. http://dx.doi.org/10.3390/v11111063.
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Familial hypercholesterolemia (FH) is an autosomal dominant disease most often caused by mutations in the low-density lipoprotein receptor (LDLR) gene, which consists of 18 exons spanning 45 kb and codes for a precursor protein of 860 amino acids. Mutations in the LDLR gene lead to a reduced hepatic clearance of LDL as well as a high risk of coronary artery disease (CAD) and sudden cardiac death (SCD). Recently, LDLR transgenes have generated interest as potential therapeutic agents. However, LDLR packaging using a lentiviral vector (LVV) system pseudotyped with a vesicular stomatitis virus (VSV)-G envelope is not efficient. In this study, we modified the LVV system to improve transduction efficiency and investigated the LDLR regions responsible for transduction inhibition. Transduction efficiency of 293T cells with a 5′-LDLReGFP-3′ fusion construct was only 1.55% compared to 42.32% for the eGFP construct. Moreover, co-expression of LDLR affected eGFP packaging. To determine the specific region of the LDLR protein responsible for packaging inhibition, we designed constructs with mutations or sequential deletions at the 3′ and 5′ ends of LDLR cDNA. All constructs except one without the ligand-binding domain (LBD) (pWoLBD–eGFP) resulted in low transduction efficiency, despite successful packaging of viral RNA in the VSV envelope, as confirmed through RT-PCR. When we evaluated a direct interaction between LDLR and the VSV envelope glycoprotein using MD simulation and protein–protein interactions, we uncovered Val119, Thr120, Thr67, and Thr118 as exposed residues in the LDLR receptor that interact with the VSV protein. Together, our results suggest that the LBD of LDLR interacts with the VSV-G protein during viral packaging, which significantly reduces transduction efficiency.
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Croston, Glenn E., Loribelle B. Milan, Keith B. Marschke, Melvin Reichman, and Michael R. Briggs. "Androgen Receptor-Mediated Antagonism of Estrogen-Dependent Low Density Lipoprotein Receptor Transcription in Cultured Hepatocytes." Endocrinology 138, no. 9 (September 1, 1997): 3779–86. http://dx.doi.org/10.1210/endo.138.9.5404.
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Abstract Postmenopausal women receiving hormone replacement therapy have a lower risk of coronary heart disease than women who do not receive hormone treatment. Multiple mechanisms are likely to underlie estrogen’s cardioprotective action, including lowering of plasma low density lipoprotein (LDL) cholesterol. Using an in vitro system exhibiting normal regulation of LDL receptor (LDLR) gene transcription, we show that 17β-estradiol activates the LDLR promoter in transiently transfected HepG2 cells. LDLR activation by estrogen in HepG2 cells is dependent on the presence of exogenous estrogen receptor, and the estrogen-responsive region of the LDLR promoter colocalizes with the sterol response element previously identified. The estrogen response is concentration dependent, saturable, and sensitive to antagonism by estrogen receptor antagonists. Further, we show that compounds with androgen receptor agonist activity attenuate the estrogen-induced up-regulation of LDLR in our model system. Progestins with androgen receptor agonist activity, such as medroxyprogesterone acetate, also suppress estrogen’s effects on LDLR expression through their androgenic properties. Characterization of the interplay between these hormone receptors on the LDLR in vitro system may allow a better understanding of the actions of sex steroids on LDLR gene expression and their roles in cardiovascular disease.
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Bordicchia, Marica, Francesco Spannella, Gianna Ferretti, Tiziana Bacchetti, Arianna Vignini, Chiara Di Pentima, Laura Mazzanti, and Riccardo Sarzani. "PCSK9 is Expressed in Human Visceral Adipose Tissue and Regulated by Insulin and Cardiac Natriuretic Peptides." International Journal of Molecular Sciences 20, no. 2 (January 9, 2019): 245. http://dx.doi.org/10.3390/ijms20020245.
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Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to and degrades the low-density lipoprotein receptor (LDLR), contributing to hypercholesterolemia. Adipose tissue plays a role in lipoprotein metabolism, but there are almost no data about PCSK9 and LDLR regulation in human adipocytes. We studied PCSK9 and LDLR regulation by insulin, atrial natriuretic peptide (ANP, a potent lipolytic agonist that antagonizes insulin), and LDL in visceral adipose tissue (VAT) and in human cultured adipocytes. PCSK9 was expressed in VAT and its expression was positively correlated with body mass index (BMI). Both intracellular mature and secreted PCSK9 were abundant in cultured human adipocytes. Insulin induced PCSK9, LDLR, and sterol-regulatory element-binding protein-1c (SREBP-1c) and -2 expression (SREBP-2). ANP reduced insulin-induced PCSK9, especially in the context of a medium simulating hyperglycemia. Human LDL induced both mature and secreted PCSK9 and reduced LDLR. ANP indirectly blocked the LDLR degradation, reducing the positive effect of LDL on PCSK9. In conclusion, PCSK9 is expressed in human adipocytes. When the expression of PCSK9 is induced, LDLR is reduced through the PCSK9-mediated degradation. On the contrary, when the induction of PCSK9 by insulin and LDL is partially blocked by ANP, the LDLR degradation is reduced. This suggests that NPs could be able to control LDLR levels, preventing PCSK9 overexpression.
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Ruotsalainen, Anna-Kaisa, Jari P. Lappalainen, Emmi Heiskanen, Mari Merentie, Virve Sihvola, Juha Näpänkangas, Line Lottonen-Raikaslehto, et al. "Nuclear factor E2-related factor 2 deficiency impairs atherosclerotic lesion development but promotes features of plaque instability in hypercholesterolaemic mice." Cardiovascular Research 115, no. 1 (June 18, 2018): 243–54. http://dx.doi.org/10.1093/cvr/cvy143.
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Abstract Aims Oxidative stress and inflammation play an important role in the progression of atherosclerosis. Transcription factor NF-E2-related factor 2 (Nrf2) has antioxidant and anti-inflammatory effects in the vessel wall, but paradoxically, global loss of Nrf2 in apoE deficient mice alleviates atherosclerosis. In this study, we investigated the effect of global Nrf2 deficiency on early and advanced atherogenesis in alternative models of atherosclerosis, LDL receptor deficient mice (LDLR−/−), and LDLR−/− mice expressing apoB-100 only (LDLR−/− ApoB100/100) having a humanized lipoprotein profile. Methods and results LDLR−/− mice were fed a high-fat diet (HFD) for 6 or 12 weeks and LDLR−/−ApoB100/100 mice a regular chow diet for 6 or 12 months. Nrf2 deficiency significantly reduced early and more advanced atherosclerosis assessed by lesion size and coverage in the aorta in both models. Nrf2 deficiency in LDLR−/− mice reduced total plasma cholesterol after 6 weeks of HFD and triglycerides in LDLR−/−ApoB100/100 mice on a chow diet. Nrf2 deficiency aggravated aortic plaque maturation in aged LDLR−/−ApoB100/100 mice as it increased plaque calcification. Moreover, ∼36% of Nrf2−/−LDLR−/−ApoB100/100 females developed spontaneous myocardial infarction (MI) or sudden death at 5 to 12 months of age. Interestingly, Nrf2 deficiency increased plaque instability index, enhanced plaque inflammation and calcification, and reduced fibrous cap thickness in brachiocephalic arteries of LDLR−/−ApoB100/100 female mice at age of 12 months. Conclusions Absence of Nrf2 reduced atherosclerotic lesion size in both atherosclerosis models, likely via systemic effects on lipid metabolism. However, Nrf2 deficiency in aged LDLR−/−ApoB100/100 mice led to an enhanced atherosclerotic plaque instability likely via increased plaque inflammation and oxidative stress, which possibly predisposed to MI and sudden death.
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Ranheim, Trine, Mari Ann Kulseth, Knut Erik Berge, and Trond Paul Leren. "Model System for Phenotypic Characterization of Sequence Variations in the LDL Receptor Gene." Clinical Chemistry 52, no. 8 (August 1, 2006): 1469–79. http://dx.doi.org/10.1373/clinchem.2006.068627.
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Abstract Background: Sequence variations in the LDL receptor (LDLR) gene cause defects of LDLR protein production and function through different molecular mechanisms. Here we describe a cell model system for the phenotypic characterization of sequence variations in the LDLR gene. Well-known sequence variations belonging to LDLR classes 2 to 5 (p.G565V, p.I161D, p.Y828C, and p.V429M) were studied in CHO and HepG2 cells. Methods: Expression of LDLR protein on the cell surface was detected by use of fluorescence-conjugated antibodies against the LDLR and the LDLR activity was measured by incubating the cells with fluorescently labeled and radiolabeled LDL. The intracellular locations of the LDLR mutants and wild-type were also investigated. Results: The class 2A p.G565V sequence variant exhibited an intracellular distribution of LDLR with no active receptors on the cell surface. Both the class 3 p.I161D and class 4 p.Y828C sequence variants gave surface staining but had a reduced ability to bind or internalize LDL, respectively. By determining the intracellular locations of the receptors we were able to visualize the accumulation of the class 5 p.V429M sequence variant in endosomes by means of a specific marker, as well as confirming that the class 4 p.Y828C variant was not localized in clathrin-coated pits. Flow cytometry allowed us quantitatively to determine the amount and activity of receptors. To confirm the results of binding and cell association of fluorescently labeled LDL analyzed by flow cytometry, assays using 125I-labeled LDL were performed. In addition to a useful and valid alternative to radiolabeled LDL, the unique properties of fluorescently labeled LDL allowed a variety of detection technologies to be used. Conclusions: This new approach enables phenotypic characterization of sequence variations in the LDLR gene. The assays developed may be valuable for confirming the pathogenicity of novel missense sequence variations found throughout the LDLR gene.
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Han, Maggie, Sarada Charugundla, Zeneng Wang, Satyesh SINHA, Zhiqiang Zhou, Hooman Allayee, Stanley Hazen, Aldons Lusis, and Diana Shih. "Abstract 4141953: Genetic deficiency of flavin containing monooxygenase 3 ( Fmo3 ) lowers circulating trimethylamine N-oxide level and protects against atherosclerosis." Circulation 150, Suppl_1 (November 12, 2024). http://dx.doi.org/10.1161/circ.150.suppl_1.4141953.
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Introduction: Our groups have previously identified trimethylamine N-oxide (TMAO) as a risk factor for cardiovascular diseases (CVD). In humans, elevated plasma TMAO levels are associated with a ~2.5-fold increased risk for major adverse cardiac events, such as death, myocardial infarction, and stroke. Bacterial metabolism of dietary choline (and L-carnitine) in the intestine leads to an intermediate, trimethylamine (TMA), which is absorbed from the gut and oxidized primarily by the hepatic flavin-containing monooxygenase 3 (FMO3) to generate TMAO. Hypothesis: We hypothesize that decreased TMAO generation caused by FMO3 deficiency in mice leads to decreased circulating TMAO levels and atherosclerosis. Approach and Results: We generated FMO3 knockout (KO) mouse on a C57BL/6J background via CRISPR/Cas9 technology. We then crossed the FMO3KO mice with LDL receptor knockout (LDLRKO) mice to generate FMO3 heterozygous (FMO3Het)/LDLRKO mice and FMO3KO/LDLRKO mice for the study. Female FMO3Het/LDLRKO and FMO3KO/LDLRKO mice were fed a 1% choline, a TMAO precursor, and 0.5% cholesterol diet for 3 months to increase circulating TMAO and total cholesterol levels. After diet feeding, FMO3KO/LDLRKO mice had 51% lower TMAO levels compared to FMO3Het/LDLRKO mice (18.3 μM vs. 38.3 μM, p < 0.0001), but no effects on plasma lipids, glucose, or insulin levels. Most notably, atherosclerotic lesion at the aortic root was decreased by 24% (p < 0.01) in the FMO3KO/LDLRKO mice as compared to the FMO3Het/LDLRKO mice. The mRNA levels of inflammatory genes, such as Cox2 and E-selectin, in the aorta were significantly decreased by more than 50% in FMO3KO/LDLRKO mice when compared to the control mice. Western blot analysis revealed decreased NF-κB activation in the aorta samples of the FMO3KO/LDLRKO mice as compared to those of the controls, suggesting reduced inflammation in the former. We also measured circulating IL-6 and TNF-α levels but did not observe any differences in plasma levels of these inflammatory biomarkers. Conclusions: Taken together, our data demonstrate that Fmo3 deficiency reduces TMAO levels and aortic lesion development in the context of an appropriate pro-atherogenic diet that contains also high levels of a TMAO precursor. These results also suggest that one mechanism for the pro-atherogenic effects of TMAO is through localized upregulation of inflammatory pathways at the level of the vessel wall, which do not necessarily manifest systemically.
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Hartman, Helen B., Douglas C. Harnish, and Mark J. Evans. "Abstract 5521: Activation of Farnesoid X Receptor (FXR) Reduces Atherosclerosis in LDLRKO and apoEKO Mice." Circulation 118, suppl_18 (October 28, 2008). http://dx.doi.org/10.1161/circ.118.suppl_18.s_566-c.
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The nuclear hormone receptors farnesoid X Receptor (FXR) and small heterodimer partner (SHP) regulate bile acid synthesis and cholesterol homeostasis in a complex fashion. In regard to atherosclerosis, FXR repression of bile acid synthesis has been proposed to be either detrimental due to reduced elimination of cholesterol or beneficial due to decreased cholesterol absorption. FXRKO mice have failed to resolved this question, with atherosclerotic lesions in FXRKO mice either enhanced (apoE, FXRdKO mice) or reduced (LDLR, FXRdKO mice). Here we demonstrate that the synthetic ligand FXR-450 blocked Western diet-mediated increases in VLDL and LDL cholesterol in both male or female LDLRKO and male or female apoEKO mice. Correspondingly, FXR-450 strongly reduced lesion development in female and male ApoEKO mice fed a Western diet. To determine if FXR-450 reduction of lipids and atherosclerotic lesion size is solely mediated by induction of SHP and repression of bile acid synthesis, LDLRKO/SHPKO and ApoEKO/SHPKO were similarly analyzed. In female LDLRKO/SHPKO or female apoEKO/SHPKO, FXR-450 no longer reduced VLDL or LDL cholesterol. Surprisingly, FXR-450 still reduced VLDL and LDL cholesterol in male LDLRKO/SHPKO and male apoEKO/SHPKO. Further FXR-450 significantly reduced lesion development in male apoEKO/SHPKO mice. These results demonstrate activation of FXR has highly beneficial effects on plasma lipids and lesion formation in multiple mouse atherosclerosis models. Further, while induction of SHP appears to be the predominant protective mechanism of FXR activation in female mice, additional mechanisms may play a role, particularly in male mice.
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Le May, Cedric, Jean Mathieu Berger, Bruno Pillot, Xavier Prieur, Eric Letessier, Xavier Collet, Anne Lespine, Bertrand Cariou, and Philippe Costet. "Abstract 22: LDLR Promotes and PCSK9 Inhibits LDL-Derived Transintestinal Cholesterol Excretion." Arteriosclerosis, Thrombosis, and Vascular Biology 32, suppl_1 (May 2012). http://dx.doi.org/10.1161/atvb.32.suppl_1.a22.
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Direct transintestinal cholesterol excretion (TICE) is an alternative path to biliary secretion and accounts for 33% of fecal cholesterol excretion in mice. Objectives: We aimed at identifying i) the lipoproteins involved in TICE ii) the role of intestinal LDL receptor (LDLR) and of its natural inhibitor, circulating proprotein convertase subtilisin kexine type 9 (PCSK9) at the basolateral pole iii) the implication of ATP binding cassette transporter ABCB1ab, a cholesterol floppase localized at the enterocytes apical side. Methods: We labelled human lipoproteins with free 3H cholesterol (free3H) or with 3H-cholesteryl oleate (3HCO). We measured lipoprotein-derived 3H-cholesterol TICE ex vivo in intestinal explants mounted in Ussing chambers. Human explants were obtained from 4 patients undergoing bariatric surgery with their informed consent. In vivo, TICE was measured in mice i.v. injected with radiolabelled lipoproteins, by cannulation of the proximal intestine and concomitant surgical bile diversion, counting radioactivity in intestinal perfusates over 120 minutes. Results: For the first time, we showed direct evidence of TICE in human duodenal explants, from both LDL and HDL. Both lipoproteins (labelled with free3H or 3HCO ) contributed to TICE in mouse explants; TICE was highly responsive to changes in temperature and medium oxygenation. LDL-derived TICE was decreased by 58% (p<0.05) in explants from LDLR knockout mice (LDLR KO), compared with control C57Bl6J. In vivo free3H- or 3HCO-LDL-derived-TICE was conserved in LDLRKO mice, suggestive of a compensatory mechanism. LDL-derived TICE was increased by 62% (p<0.01) in PCSK9KO that present with ∼300% more intestinal LDLR. Acute depletion of intestinal LDLR with purified recombinant PCSK9 (i.v.) led to 40% (p<0.05) less TICE in PCSK9KO but had no effect in LDLRKO, confirming the implication of this receptor. Lovastatin (0.02% W/W 10d) increased TICE by 71% (p < 0.05) in C57Bl6J but not in LDLRKO. Interestingly, using 3H-cholesterol diluted in intralipid as a source, we showed that ABCB1 plays an important role in TICE. Indeed ABCB1ab -/- mice presented with 26% (p<0.05) less TICE than FVB controls in vivo and ABCB1 inhibitor PSC-833 (5mircoM) decreased TICE by 64% in an ABCB1 dependent fashion in explants. Collectively, these results provide the first molecular understanding of TICE.
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Bi, Xin, Xuewei Zhu, Chuan Gao, Qiang Cao, Mingxia Liu, Swapnil Shewale, Elena Boudyguina, Martha Wilson, and John Parks. "Abstract 49: Myeloid Cell Specific ABCA1 Deletion Does Not Significantly Accelerate Atherogenesis in LDL Receptor Knockout Mice." Arteriosclerosis, Thrombosis, and Vascular Biology 33, suppl_1 (May 2013). http://dx.doi.org/10.1161/atvb.33.suppl_1.a49.
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ATP binding cassette transporter A1 (ABCA1) functions as a cellular cholesterol exporter. Macrophage ABCA1 expression is important in reducing cellular cholesterol content and inflammatory response. Bone marrow (BM) transplantation studies suggest that leukocyte ABCA1 protects against atherosclerosis development. However, the in vivo effect of macrophage ABCA1 in atherogenesis is not fully understood due to the presence in BM of other leukocyte populations. Myeloid[[Unable to Display Character: ‐]]Specific ABCA1 Knockout (MSKO) mice in the LDL receptor knockout (LDLrKO) C57BL/6 background were developed to address this question. MSKO/LDLrKO (DKO) and LDLrKO (SKO) mice were fed chow or an atherogenic diet for 10-24wk to examine early to advanced stages of atherosclerosis. Basal (i.e. chow) plasma lipid levels were similar between genotypes, but relative to SKO mice, DKO mice had reduced plasma apoB[[Unable to Display Character: ‐]]containing lipoprotein (apoB Lp) levels throughout the diet-induced atherosclerosis progression phase resulting from decreased hepatic VLDL secretion. Despite a significant reduction in plasma apoB Lp levels, chow and atherogenic diet fed DKO mice had significantly higher cholesterol content in resident peritoneal macrophages and higher plasma proinflammatory cytokine and chemokine levels during atherogenic diet[[Unable to Display Character: ‐]]feeding compared to SKO mice. Aortic cholesterol content was similar between genotypes at early (i.e. 24wk chow-fed) or intermediate (i.e. atherogenic diet for 10wk or 16wk) stages and slightly increased at late stage atherosclerosis (i.e. 24wk atherogenic diet). Aortic root lesion area was also similar for both genotypes after 16wk of atherosclerosis induction. Transplantation of DKO or SKO BM into SKO mice followed by 16wk atherogenic diet feeding also showed similar extent of atherosclerosis. Collectively, these results suggest a novel role for myeloid cell ABCA1 in increasing hepatic VLDL secretion and plasma apoB Lp concentrations in atherogenic diet fed LDLrKO mice that offsets its atheroprotective role in decreasing macrophage cholesterol content and inflammatory response, resulting in no increase in atherosclerosis in its absence.