LDL receptor

Last updated

LDLR
Protein LDLR PDB 1ajj.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases LDLR , FH, FHC, LDLCQ2, low density lipoprotein receptor, FHCL1
External IDs OMIM: 606945; MGI: 96765; HomoloGene: 55469; GeneCards: LDLR; OMA:LDLR - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001252658
NM_001252659
NM_010700

RefSeq (protein)

NP_000518
NP_001182727
NP_001182728
NP_001182729
NP_001182732

NP_001239587
NP_001239588
NP_034830

Location (UCSC) Chr 19: 11.09 – 11.13 Mb Chr 9: 21.63 – 21.66 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

The low-density lipoprotein receptor (LDL-R) is a mosaic protein of 839 amino acids (after removal of 21-amino acid signal peptide) [5] that mediates the endocytosis of cholesterol-rich low-density lipoprotein (LDL). It is a cell-surface receptor that recognizes apolipoprotein B100 (ApoB100), which is embedded in the outer phospholipid layer of very low-density lipoprotein (VLDL), their remnantsi.e. intermediate-density lipoprotein (IDL), and LDL particles. The receptor also recognizes apolipoprotein E (ApoE) which is found in chylomicron remnants and IDL. In humans, the LDL receptor protein is encoded by the LDLR gene on chromosome 19. [6] [7] [8] It belongs to the low density lipoprotein receptor gene family. [9] It is most significantly expressed in bronchial epithelial cells and adrenal gland and cortex tissue. [10]

Michael S. Brown and Joseph L. Goldstein were awarded the 1985 Nobel Prize in Physiology or Medicine for their identification of LDL-R [11] and its relation to cholesterol metabolism and familial hypercholesterolemia. [12] Disruption of LDL-R can lead to higher LDL-cholesterol as well as increasing the risk of related diseases. Individuals with disruptive mutations (defined as nonsense, splice site, or indel frameshift) in LDLR have an average LDL-cholesterol of 279 mg/dL, compared with 135 mg/dL for individuals with neither disruptive nor deleterious mutations. Disruptive mutations were 13 times more common in individuals with early-onset myocardial infarction or coronary artery disease than in individuals without either disease. [13]

Structure

Gene

The LDLR gene resides on chromosome 19 at the band 19p13.2 and is split into 18 exons. [8] Exon 1 contains a signal sequence that localises the receptor to the endoplasmic reticulum for transport to the cell surface. Beyond this, exons 2-6 code the ligand binding region; 7-14 code the epidermal growth factor (EGF) domain; 15 codes the oligosaccharide rich region; 16 (and some of 17) code the membrane spanning region; and 18 (with the rest of 17) code the cytosolic domain.

This gene produces 6 isoforms through alternative splicing. [14]

Protein

This protein belongs to the LDLR family and is made up of a number of functionally distinct domains, including 3 EGF-like domains, 7 LDL-R class A domains, and 6 LDL-R class B repeats. [14]

The N-terminal domain of the LDL receptor, which is responsible for ligand binding, is composed of seven sequence repeats (~50% identical). Each repeat, referred to as a class A repeat or LDL-A, contains roughly 40 amino acids, including 6 cysteine residues that form disulfide bonds within the repeat. Additionally, each repeat has highly conserved acidic residues which it uses to coordinate a single calcium ion in an octahedral lattice. Both the disulfide bonds and calcium coordination are necessary for the structural integrity of the domain during the receptor's repeated trips to the highly acidic interior of the endosome. The exact mechanism of interaction between the class A repeats and ligand (LDL) is unknown, but it is thought that the repeats act as "grabbers" to hold the LDL. Binding of ApoB requires repeats 2-7 while binding ApoE requires only repeat 5 (thought to be the ancestral repeat).

Next to the ligand binding domain is an EGF precursor homology domain (EGFP domain). This shows approximately 30% homology with the EGF precursor gene. There are three "growth factor" repeats; A, B and C. A and B are closely linked while C is separated by the YWTD repeat region, which adopts a beta-propeller conformation (LDL-R class B domain). It is thought that this region is responsible for the pH-dependent conformational shift that causes bound LDL to be released in the endosome.

A third domain of the protein is rich in O-linked oligosaccharides but appears to show little function. Knockout experiments have confirmed that no significant loss of activity occurs without this domain. It has been speculated that the domain may have ancestrally acted as a spacer to push the receptor beyond the extracellular matrix.

The single transmembrane domain of 22 (mostly) non-polar residues crosses the plasma membrane in a single alpha helix.

The cytosolic C-terminal domain contains ~50 amino acids, including a signal sequence important for localizing the receptors to clathrin-coated pits and for triggering receptor-mediated endocytosis after binding. Portions of the cytosolic sequence have been found in other lipoprotein receptors, as well as in more distant receptor relatives. [15] [16] [17]

Mutations

Loss-of-function mutations in the gene encoding the LDL receptor are known to cause familial hypercholesterolaemia.

There are 5 broad classes of mutation of the LDL receptor:

Gain-of-function mutations decrease LDL levels and are a target of research to develop a gene therapy to treat refractory hypercholesterolemia. [19]

Function

LDL receptor mediates the endocytosis of cholesterol-rich LDL and thus maintains the plasma level of LDL. [20] This occurs in all nucleated cells, but mainly in the liver which removes ~70% of LDL from the circulation. LDL receptors are clustered in clathrin-coated pits, and coated pits pinch off from the surface to form coated endocytic vesicles that carry LDL into the cell. [21] After internalization, the receptors dissociate from their ligands when they are exposed to lower pH in endosomes. After dissociation, the receptor folds back on itself to obtain a closed conformation and recycles to the cell surface. [22] The rapid recycling of LDL receptors provides an efficient mechanism for delivery of cholesterol to cells. [23] [24] It was also reported that by association with lipoprotein in the blood, viruses such as hepatitis C virus, Flaviviridae viruses and bovine viral diarrheal virus could enter cells indirectly via LDLR-mediated endocytosis. [25] LDLR has been identified as the primary mode of entry for the Vesicular stomatitis virus in mice and humans. [26] In addition, LDLR modulation is associated with early atherosclerosis-related lymphatic dysfunction. [27] Synthesis of receptors in the cell is regulated by the level of free intracellular cholesterol; if it is in excess for the needs of the cell then the transcription of the receptor gene will be inhibited. [28] LDL receptors are translated by ribosomes on the endoplasmic reticulum and are modified by the Golgi apparatus before travelling in vesicles to the cell surface.

Clinical significance

In humans, LDL is directly involved in the development of atherosclerosis, which is the process responsible for the majority of cardiovascular diseases, due to accumulation of LDL-cholesterol in the blood [ citation needed ]. Hyperthyroidism may be associated with reduced cholesterol via upregulation of the LDL receptor, and hypothyroidism with the converse. A vast number of studies have described the relevance of LDL receptors in the pathophysiology of atherosclerosis, metabolic syndrome, and steatohepatitis. [29] [30] Previously, rare mutations in LDL-genes have been shown to contribute to myocardial infarction risk in individual families, whereas common variants at more than 45 loci have been associated with myocardial infarction risk in the population. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. [31] Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III. [32] [33] Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk. Overall, LDLR has a high clinical relevance in blood lipids. [34] [35]

Clinical marker

A multi-locus genetic risk score study based on a combination of 27 loci, including the LDLR gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmö Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22). [36]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

[[File:
StatinPathway WP430.png go to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to article
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
StatinPathway WP430.png go to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to article
|alt=Statin pathway edit]]
Statin pathway edit
  1. The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".

Related Research Articles

<span class="mw-page-title-main">Cholesterol</span> Sterol biosynthesized by all animal cells

Cholesterol is the principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils.

<span class="mw-page-title-main">HMG-CoA reductase</span> Mammalian protein found in Homo sapiens

HMG-CoA reductase is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids. HMGCR catalyzes the conversion of HMG-CoA to mevalonic acid, a necessary step in the biosynthesis of cholesterol. Normally in mammalian cells this enzyme is competitively suppressed so that its effect is controlled. This enzyme is the target of the widely available cholesterol-lowering drugs known collectively as the statins, which help treat dyslipidemia.

<span class="mw-page-title-main">Michael Stuart Brown</span> American geneticist and Nobel laureate (born 1941)

Michael Stuart Brown ForMemRS NAS AAA&S APS is an American geneticist and Nobel laureate. He was awarded the Nobel Prize in Physiology or Medicine with Joseph L. Goldstein in 1985 for describing the regulation of cholesterol metabolism.

Scavenger receptors are a large and diverse superfamily of cell surface receptors. Its properties were first recorded in 1970 by Drs. Brown and Goldstein, with the defining property being the ability to bind and remove modified low density lipoproteins (LDL). Today scavenger receptors are known to be involved in a wide range of processes, such as: homeostasis, apoptosis, inflammatory diseases and pathogen clearance. Scavenger receptors are mainly found on myeloid cells and other cells that bind to numerous ligands, primarily endogenous and modified host-molecules together with pathogen-associated molecular patterns(PAMPs), and remove them. The Kupffer cells in the liver are particularly rich in scavenger receptors, includes SR-A I, SR-A II, and MARCO.

<span class="mw-page-title-main">Apolipoprotein B</span> Protein-coding gene in the species Homo sapiens

Apolipoprotein B (ApoB) is a protein that in humans is encoded by the APOB gene. It is commonly used to detect risk of atherosclerotic cardiovascular disease.

<span class="mw-page-title-main">Beta-propeller</span> Toroid protein structure formed from beta sheets

In structural biology, a beta-propeller (β-propeller) is a type of all-β protein architecture characterized by 4 to 8 highly symmetrical blade-shaped beta sheets arranged toroidally around a central axis. Together the beta-sheets form a funnel-like active site.

<span class="mw-page-title-main">Low-density lipoprotein receptor gene family</span>

The low-density lipoprotein receptor gene family codes for a class of structurally related cell surface receptors that fulfill diverse biological functions in different organs, tissues, and cell types. The role that is most commonly associated with this evolutionarily ancient family is cholesterol homeostasis. In humans, excess cholesterol in the blood is captured by low-density lipoprotein (LDL) and removed by the liver via endocytosis of the LDL receptor. Recent evidence indicates that the members of the LDL receptor gene family are active in the cell signalling pathways between specialized cells in many, if not all, multicellular organisms.

<span class="mw-page-title-main">VLDL receptor</span> Protein-coding gene in the species Homo sapiens

The very-low-density-lipoprotein receptor (VLDLR) is a transmembrane lipoprotein receptor of the low-density-lipoprotein (LDL) receptor family. VLDLR shows considerable homology with the members of this lineage. Discovered in 1992 by T. Yamamoto, VLDLR is widely distributed throughout the tissues of the body, including the heart, skeletal muscle, adipose tissue, and the brain, but is absent from the liver. This receptor has an important role in cholesterol uptake, metabolism of apolipoprotein E-containing triacylglycerol-rich lipoproteins, and neuronal migration in the developing brain. In humans, VLDLR is encoded by the VLDLR gene. Mutations of this gene may lead to a variety of symptoms and diseases, which include type I lissencephaly, cerebellar hypoplasia, and atherosclerosis.

<span class="mw-page-title-main">Foam cell</span> Fat-laden M2 macrophages seen in atherosclerosis

Foam cells, also called lipid-laden macrophages, are a type of cell that contain cholesterol. These can form a plaque that can lead to atherosclerosis and trigger myocardial infarction and stroke.

<span class="mw-page-title-main">Familial hypercholesterolemia</span> Genetic disorder characterized by high cholesterol levels

Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein cholesterol, in the blood and early cardiovascular diseases. The most common mutations diminish the number of functional LDL receptors in the liver or produce abnormal LDL receptors that never go to the cell surface to function properly. Since the underlying body biochemistry is slightly different in individuals with FH, their high cholesterol levels are less responsive to the kinds of cholesterol control methods which are usually more effective in people without FH. Nevertheless, treatment is usually effective.

<span class="mw-page-title-main">LDL-receptor-related protein-associated protein</span> Protein-coding gene in the species Homo sapiens

Low density lipoprotein receptor-related protein-associated protein 1 also known as LRPAP1 or RAP is a chaperone protein which in humans is encoded by the LRPAP1 gene.

<span class="mw-page-title-main">Low-density lipoprotein receptor-related protein 8</span> Cell surface receptor, part of the low-density lipoprotein receptor family

Low-density lipoprotein receptor-related protein 8 (LRP8), also known as apolipoprotein E receptor 2 (ApoER2), is a protein that in humans is encoded by the LRP8 gene. ApoER2 is a cell surface receptor that is part of the low-density lipoprotein receptor family. These receptors function in signal transduction and endocytosis of specific ligands. Through interactions with one of its ligands, reelin, ApoER2 plays an important role in embryonic neuronal migration and postnatal long-term potentiation. Another LDL family receptor, VLDLR, also interacts with reelin, and together these two receptors influence brain development and function. Decreased expression of ApoER2 is associated with certain neurological diseases.

<span class="mw-page-title-main">SREBP cleavage-activating protein</span> Protein-coding gene in the species Homo sapiens

Sterol regulatory element-binding protein cleavage-activating protein, also known as SREBP cleavage-activating protein or SCAP, is a protein that in humans is encoded by the SCAP gene.

The epididymal secretory protein E1, also known as NPC2, is one of two main lysosomal transport proteins that assist in the regulation of cellular cholesterol by exportation of LDL-derived cholesterol from lysosomes. Lysosomes have digestive enzymes that allow it to break down LDL particles to LDL-derived cholesterol once the LDL particle is engulfed into the cell via receptor mediated endocytosis.

<span class="mw-page-title-main">OLR1</span> Protein-coding gene in the species Homo sapiens

Oxidized low-density lipoprotein receptor 1 also known as lectin-type oxidized LDL receptor 1 (LOX-1) is a protein that in humans is encoded by the OLR1 gene.

<span class="mw-page-title-main">LRP2</span> Mammalian protein found in Homo sapiens

Low density lipoprotein receptor-related protein 2 also known as LRP-2 or megalin is a protein which in humans is encoded by the LRP2 gene.

<span class="mw-page-title-main">LRP1</span> Mammalian protein found in Homo sapiens

Low density lipoprotein receptor-related protein 1 (LRP1), also known as alpha-2-macroglobulin receptor (A2MR), apolipoprotein E receptor (APOER) or cluster of differentiation 91 (CD91), is a protein forming a receptor found in the plasma membrane of cells involved in receptor-mediated endocytosis. In humans, the LRP1 protein is encoded by the LRP1 gene. LRP1 is also a key signalling protein and, thus, involved in various biological processes, such as lipoprotein metabolism and cell motility, and diseases, such as neurodegenerative diseases, atherosclerosis, and cancer.

<span class="mw-page-title-main">PCSK9</span> Mammalian protein found in humans

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the PCSK9 gene in humans on chromosome 1. It is the 9th member of the proprotein convertase family of proteins that activate other proteins. Similar genes (orthologs) are found across many species. As with many proteins, PCSK9 is inactive when first synthesized, because a section of peptide chains blocks their activity; proprotein convertases remove that section to activate the enzyme. The PCSK9 gene also contains one of 27 loci associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">Low-density lipoprotein receptor adapter protein 1</span> Protein-coding gene in the species Homo sapiens

Low-density lipoprotein receptor adapter protein 1 is a protein that in humans is encoded by the LDLRAP1 gene.

YWTD repeats are four-stranded beta-propeller repeats found in low-density lipoprotein receptors (LDLR). The six YWTD repeats together fold into a six-bladed beta-propeller. Each blade of the propeller consists of four antiparallel beta-strands; the innermost strand of each blade is labeled 1 and the outermost strand, 4. The sequence repeats are offset with respect to the blades of the propeller, such that any given 40-residue YWTD repeat spans strands 24 of one propeller blade and strand 1 of the subsequent blade. This offset ensures circularization of the propeller because the last strand of the final sequence repeat acts as an innermost strand 1 of the blade that harbors strands 24 from the first sequence repeat. The repeat is found in a variety of proteins that include, vitellogenin receptor from Drosophila melanogaster, low-density lipoprotein (LDL) receptor, preproepidermal growth factor, and nidogen (entactin).

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000130164 Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000032193 Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Südhof TC, Goldstein JL, Brown MS, Russell DW (May 1985). "The LDL receptor gene: a mosaic of exons shared with different proteins". Science. 228 (4701): 815–22. Bibcode:1985Sci...228..815S. doi:10.1126/science.2988123. PMC   4450672 . PMID   2988123.
  6. Francke U, Brown MS, Goldstein JL (May 1984). "Assignment of the human gene for the low density lipoprotein receptor to chromosome 19: synteny of a receptor, a ligand, and a genetic disease". Proceedings of the National Academy of Sciences of the United States of America. 81 (9): 2826–30. Bibcode:1984PNAS...81.2826F. doi: 10.1073/pnas.81.9.2826 . PMC   345163 . PMID   6326146.
  7. Lindgren V, Luskey KL, Russell DW, Francke U (December 1985). "Human genes involved in cholesterol metabolism: chromosomal mapping of the loci for the low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl-coenzyme A reductase with cDNA probes". Proceedings of the National Academy of Sciences of the United States of America. 82 (24): 8567–71. Bibcode:1985PNAS...82.8567L. doi: 10.1073/pnas.82.24.8567 . PMC   390958 . PMID   3866240.
  8. 1 2 "LDLR low density lipoprotein receptor [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2016-10-10.
  9. Nykjaer A, Willnow TE (June 2002). "The low-density lipoprotein receptor gene family: a cellular Swiss army knife?". Trends in Cell Biology. 12 (6): 273–80. doi:10.1016/S0962-8924(02)02282-1. PMID   12074887.
  10. "BioGPS - your Gene Portal System". biogps.org. Retrieved 2016-10-10.
  11. "The Nobel Prize in Physiology or Medicine 1985" (Press release). The Royal Swedish Academy of Science. 1985. Retrieved 2010-07-01.
  12. Brown MS, Goldstein JL (November 1984). "How LDL receptors influence cholesterol and atherosclerosis". Scientific American. 251 (5): 58–66. Bibcode:1984SciAm.251c..52K. doi:10.1038/scientificamerican0984-52. PMID   6390676.
  13. Do R, Stitziel NO, Won HH, Jørgensen AB, Duga S, Angelica Merlini P, et al. (February 2015). "Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction". Nature. 518 (7537): 102–6. Bibcode:2015Natur.518..102.. doi:10.1038/nature13917. PMC   4319990 . PMID   25487149.
  14. 1 2 "LDLR - Low-density lipoprotein receptor precursor - Homo sapiens (Human) - LDLR gene & protein". www.uniprot.org. Retrieved 2016-10-10.
  15. Yamamoto T, Davis CG, Brown MS, Schneider WJ, Casey ML, Goldstein JL, et al. (November 1984). "The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA". Cell. 39 (1): 27–38. doi:10.1016/0092-8674(84)90188-0. PMID   6091915. S2CID   25822170.
  16. Brown MS, Herz J, Goldstein JL (August 1997). "LDL-receptor structure. Calcium cages, acid baths and recycling receptors". Nature. 388 (6643): 629–30. Bibcode:1997Natur.388..629B. doi: 10.1038/41672 . PMID   9262394. S2CID   33590160.
  17. Gent J, Braakman I (October 2004). "Low-density lipoprotein receptor structure and folding". Cellular and Molecular Life Sciences. 61 (19–20): 2461–70. doi:10.1007/s00018-004-4090-3. PMID   15526154. S2CID   21235282.
  18. "Low Density Lipoprotein Receptor". LOVD v.1.1.0 - Leiden Open Variation Database. Archived from the original on 2016-01-28. Retrieved 2013-10-17.
  19. Srivastava RA (December 2023). "New opportunities in the management and treatment of refractory hypercholesterolemia using in vivo CRISPR-mediated genome/base editing". Nutrition, Metabolism and Cardiovascular Diseases. 33 (12): 2317–2325. doi:10.1016/j.numecd.2023.08.010. PMID   37805309.
  20. Leren TP (November 2014). "Sorting an LDL receptor with bound PCSK9 to intracellular degradation". Atherosclerosis. 237 (1): 76–81. doi:10.1016/j.atherosclerosis.2014.08.038. PMID   25222343.
  21. Goldstein JL, Brown MS (April 2009). "The LDL receptor". Arteriosclerosis, Thrombosis, and Vascular Biology. 29 (4): 431–8. doi:10.1161/ATVBAHA.108.179564. PMC   2740366 . PMID   19299327.
  22. Rudenko G, Henry L, Henderson K, Ichtchenko K, Brown MS, Goldstein JL, et al. (December 2002). "Structure of the LDL receptor extracellular domain at endosomal pH". Science. 298 (5602): 2353–8. Bibcode:2002Sci...298.2353R. doi: 10.1126/science.1078124 . PMID   12459547. S2CID   17712211.
  23. Basu SK, Goldstein JL, Anderson RG, Brown MS (May 1981). "Monensin interrupts the recycling of low density lipoprotein receptors in human fibroblasts". Cell. 24 (2): 493–502. doi:10.1016/0092-8674(81)90340-8. PMID   6263497. S2CID   29553611.
  24. Brown MS, Anderson RG, Goldstein JL (March 1983). "Recycling receptors: the round-trip itinerary of migrant membrane proteins". Cell. 32 (3): 663–7. doi:10.1016/0092-8674(83)90052-1. PMID   6299572. S2CID   34919831.
  25. Agnello V, Abel G, Elfahal M, Knight GB, Zhang QX (October 1999). "Hepatitis C virus and other flaviviridae viruses enter cells via low density lipoprotein receptor". Proceedings of the National Academy of Sciences of the United States of America. 96 (22): 12766–71. Bibcode:1999PNAS...9612766A. doi: 10.1073/pnas.96.22.12766 . PMC   23090 . PMID   10535997.
  26. Finkelshtein D, Werman A, Novick D, Barak S, Rubinstein M (April 2013). "LDL receptor and its family members serve as the cellular receptors for vesicular stomatitis virus". Proceedings of the National Academy of Sciences of the United States of America. 110 (18): 7306–11. Bibcode:2013PNAS..110.7306F. doi: 10.1073/pnas.1214441110 . PMC   3645523 . PMID   23589850.
  27. Milasan A, Dallaire F, Mayer G, Martel C (2016-01-01). "Effects of LDL Receptor Modulation on Lymphatic Function". Scientific Reports. 6: 27862. Bibcode:2016NatSR...627862M. doi:10.1038/srep27862. PMC   4899717 . PMID   27279328.
  28. Smith JR, Osborne TF, Goldstein JL, Brown MS (Feb 1990). "Identification of nucleotides responsible for enhancer activity of sterol regulatory element in low density lipoprotein receptor gene". The Journal of Biological Chemistry. 265 (4): 2306–10. doi: 10.1016/S0021-9258(19)39976-4 . PMID   2298751. S2CID   26062629.
  29. Hsieh J, Koseki M, Molusky MM, Yakushiji E, Ichi I, Westerterp M, et al. (July 2016). "TTC39B deficiency stabilizes LXR reducing both atherosclerosis and steatohepatitis". Nature. 535 (7611): 303–7. Bibcode:2016Natur.535..303H. doi:10.1038/nature18628. PMC   4947007 . PMID   27383786.
  30. Walter K, Min JL, Huang J, Crooks L, Memari Y, McCarthy S, et al. (October 2015). "The UK10K project identifies rare variants in health and disease". Nature. 526 (7571): 82–90. Bibcode:2015Natur.526...82T. doi:10.1038/nature14962. PMC   4773891 . PMID   26367797.
  31. Rose-Hellekant TA, Schroeder MD, Brockman JL, Zhdankin O, Bolstad R, Chen KS, et al. (August 2007). "Estrogen receptor-positive mammary tumorigenesis in TGFalpha transgenic mice progresses with progesterone receptor loss". Oncogene. 26 (36): 5238–46. doi:10.1038/sj.onc.1210340. PMC   2587149 . PMID   17334393.
  32. Crosby J, Peloso GM, Auer PL, Crosslin DR, Stitziel NO, Lange LA, et al. (July 2014). "Loss-of-function mutations in APOC3, triglycerides, and coronary disease". The New England Journal of Medicine. 371 (1): 22–31. doi:10.1056/NEJMoa1307095. PMC   4180269 . PMID   24941081.
  33. Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A (July 2014). "Loss-of-function mutations in APOC3 and risk of ischemic vascular disease". The New England Journal of Medicine. 371 (1): 32–41. doi: 10.1056/NEJMoa1308027 . PMID   24941082. S2CID   26995834.
  34. Shuldiner AR, Pollin TI (August 2010). "Genomics: Variations in blood lipids". Nature. 466 (7307): 703–4. Bibcode:2010Natur.466..703S. doi: 10.1038/466703a . PMID   20686562. S2CID   205057802.
  35. Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, et al. (August 2010). "Biological, clinical and population relevance of 95 loci for blood lipids". Nature. 466 (7307): 707–13. Bibcode:2010Natur.466..707T. doi:10.1038/nature09270. PMC   3039276 . PMID   20686565.
  36. Mega JL, Stitziel NO, Smith JG, Chasman DI, Caulfield MJ, Devlin JJ, et al. (June 2015). "Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials". Lancet. 385 (9984): 2264–71. doi:10.1016/S0140-6736(14)61730-X. PMC   4608367 . PMID   25748612.

Further reading