VLDLR
   HOME

TheInfoList



OR:

The very-low-density-lipoprotein receptor (VLDLR) is a
transmembrane A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently u ...
lipoprotein A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, sur ...
receptor of the low-density-lipoprotein (LDL) receptor family. VLDLR shows considerable homology with the members of this lineage. Discovered in 1992 by Tokuo. Yamamoto and Sadao. Takahashi, VLDLR is widely distributed throughout the tissues of the body, including the heart,
skeletal muscle Skeletal muscle (commonly referred to as muscle) is one of the three types of vertebrate muscle tissue, the others being cardiac muscle and smooth muscle. They are part of the somatic nervous system, voluntary muscular system and typically are a ...
,
adipose tissue Adipose tissue (also known as body fat or simply fat) is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, Blood vessel, vascular endothel ...
, and the brain, but is absent from the liver. This receptor has an important role in cholesterol uptake, metabolism of
apolipoprotein E Apolipoprotein E (Apo-E) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular diseases. It is encoded in humans by the gene ''APOE''. Apo-E belongs to a family ...
-containing
triacylglycerol A triglyceride (from ''tri-'' and '' glyceride''; also TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids. Triglycerides are the main constituents of body fat in humans and other vertebrates as ...
-rich lipoproteins, and
neuronal migration The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The field ...
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 Lissencephaly (, meaning 'smooth brain') is a set of rare brain disorders whereby the whole or parts of the surface of the brain are smooth. It is caused by defective neuronal migration during the 12th to 24th weeks of gestation, resulting in a ...
,
cerebellar hypoplasia Cerebellar hypoplasia is characterized by reduced cerebellar volume, even though cerebellar shape is (near) normal. It consists of a heterogeneous group of disorders of cerebellum, cerebellar maldevelopment presenting as early-onset Non-progress ...
, and
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
.


Protein structure

VLDLR is a member of the low-density-lipoprotein (LDL) receptor family, which is entirely composed of type I
transmembrane A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently u ...
lipoprotein A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, sur ...
receptors. All members of this family share five highly conserved structural domains: an extracellular N-terminal
ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...
-binding domain with cysteine-rich repeats (also called ligand-binding repeats), an epidermal growth factor (EGF), an
O-linked glycosylation ''O''-linked glycosylation is the attachment of a sugar molecule to the oxygen atom of serine (Ser) or threonine (Thr) residues in a protein. ''O''-glycosylation is a post-translational modification that occurs after the protein has been synthesis ...
sugar domain, a single transmembrane sequence, and a cytoplasmic domain which contains an NPxY sequence. The NPxY motif functions in signal transduction and the targeting of receptors to coated pits and consists of the sequence Asparagine-Proline-X-Tyrosine, where X can be any amino acid. Mimicking this general structure, VLDLR has eight, 40 amino acid long cysteine-rich repeats in its extracellular N-terminal ligand-binding domain. This is the main difference from the main member of the LDL receptor family, LDLR, which has only seven cysteine-rich repeats which are also 40 amino acids long. Each of these cysteine-rich repeats, in both VLDLR and LDLR, has three disulfide bonds and a coordinated Ca2+ ion. The N-terminus also consists of a glycine residue followed by 27
hydrophobic In chemistry, hydrophobicity is the chemical property of a molecule (called a hydrophobe) that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, thu ...
residues that constitute the
signal peptide A signal peptide (sometimes referred to as signal sequence, targeting signal, localization signal, localization sequence, transit peptide, leader sequence or leader peptide) is a short peptide (usually 16–30 amino acids long) present at the ...
. Following this region is an EGF repeat, a
β-propeller In structural biology, a beta-propeller (β-propeller) is a type of all-β protein fold, all-β protein architecture characterized by 4 to 8 highly symmetrical blade-shaped beta sheets arranged toroidally around a central axis. Together the beta-s ...
segment that plays a role in the pH-dependent dissociation of the ligand-receptor complex, and two more EGF repeats. The VLDLR O-linked glycosylation domain, next in the sequence, has many threonine and serine residues and totals 46 amino acids. The transmembrane domain, which functions in anchoring the receptors to the membrane, is 22 amino acids long. Final in the sequence is the 54 amino acid cytoplasmic domain, which contains the NPxY motif.


Isoforms

The full-length human VLDLR genome is located on locus 9p24 on chromosome 9. It consists of a 40 kb segment that includes 19
exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...
-coding sequences, which is one more exon than encoded by LDLR. This extra exon in the ''VLDLR'' gene accounts for the extra cysteine-binding repeat not found in LDLR. Together, the exons making up the ''VLDLR'' gene encode a protein that is 873 amino acid residues long. VLDLR is known to exist as four different
protein isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...
s: type I, II, III, and IV. These different isoforms result from variations in
alternative splicing Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...
. The transcript of type I VLDLR (VLDLR-I) is composed of all 19 exons. VLDLR-II, on the other hand, lacks exon 16, which encodes for the
O-glycosylation ''O''-linked glycosylation is the attachment of a sugar molecule to the oxygen atom of serine (Ser) or threonine (Thr) residues in a protein. ''O''-glycosylation is a post-translational modification that occurs after the protein has been synthesis ...
domain between sugar regions. VLDLR-III lacks exon 4 that encodes the third
ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...
-binding repeat. Finally, VLDLR-IV transcripts lack both exon 16 and exon 4. It has been shown that 75% of VLDLR transcripts exist as isoform type II in
mouse brain A mouse (: mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus'' ...
models. This shows that most VLDLRs in the brain are not glycosylated, as type II lacks exon 16 which encodes the O-glycosylation domain. Isoform type IV is known to be the second most prominent.


Evolutionary conservation

There is a high level of conservation within the LDL receptor family. In particular, there is 50% overall sequence homology between VLDLR and
ApoER2 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 lipopr ...
, another
lipoprotein A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, sur ...
receptor of this family. Comparing LDLR and VLDLR, it was found that their
primary structures Primary Structures: Younger American and British Sculptors was an exhibition presented by the Jewish Museum in New York City from April 27 to June 12 in 1966. The show was a survey of recent work in sculpture by artists from the Northeast United S ...
are 55% identical within their
ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...
-binding regions. The modular structures of these two proteins are almost superimposable, with the only difference being the additional cysteine-rich repeat in VLDLR. This is demonstrated through the alignment of the two receptors according to their linker region; in LDLR, the linker region is located between cysteine-rich repeats four and five of its seven repeats while in VLDLR, the linker region appears to be between repeats five and six of its eight repeats. VLDLR also shows high homology among various species. VLDLR of humans, mice, rats, and rabbits have been identified as 95% identical. Furthermore, there is approximately 84% conservation with the respective protein in chickens. This level of homology between species is much higher than that found for LDLR. Hence, these gene comparisons suggest that VLDLR and LDLR diverged before the LDLRs did among vertebrates.


Ligand binding

VLDLR binds compounds containing
apolipoprotein E Apolipoprotein E (Apo-E) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular diseases. It is encoded in humans by the gene ''APOE''. Apo-E belongs to a family ...
(apoE). These
ligands In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ...
attach to the cysteine binding repeats in the N-terminus end. The difference in cysteine-rich repeats between the members of the LDL receptor family lead to the differences in binding affinity. VLDLR, in particular, binds
VLDL Very-low-density lipoprotein (VLDL), density relative to extracellular water, is a type of lipoprotein made by the liver. VLDL is one of the five major groups of lipoproteins (chylomicrons, VLDL, intermediate-density lipoprotein, LDL, low-density ...
and
intermediate-density lipoprotein Intermediate-density lipoproteins (IDLs) belong to the lipoprotein particle family and are formed from the degradation of very low-density lipoproteins as well as high-density lipoproteins. IDL is one of the five major groups of lipoproteins (chylo ...
(IDL), but not
LDL Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall densit ...
. This inability to bind LDL is due to VLDLR's incapability to bind
apolipoprotein B Apolipoprotein B (ApoB) is a protein that in humans is encoded by the gene. Its measurement is commonly used to detect the risk of Atherosclerosis, atherosclerotic Coronary artery disease, cardiovascular disease. Isoforms The protein occur ...
(apoB), which is present in LDL.


Inhibitors

Receptor-associated protein (RAP) and
thrombospondin-1 Thrombospondin 1, abbreviated as THBS1, is a protein that in humans is encoded by the ''THBS1'' gene. Thrombospondin 1 is a subunit of a disulfide-linked homotrimeric protein. This protein is an adhesive glycoprotein that mediates cell-to-cell ...
(THBS1) have been identified as compounds that bind VLDLR. In many cases, these compounds exhibit inhibitory effects. THBS1 binds VLDLR and blocks ligand binding. This plays an important role in the
reelin Reelin, encoded by the ''RELN'' gene, is a large secreted extracellular matrix glycoprotein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell–cell interactions. Besides this importa ...
pathway, as THBS1 can block the attachment of reelin, while simultaneously stimulating the
transcription factors In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fun ...
normally activated by reelin. This binding of THBS1, however, does not induce the subsequent degradation of these transcription factors, as reelin does, and can thus lead to greatly amplified effects. The RAP protein acts similarly by blocking reelin from binding VLDLR. However, in this case phosphorylation of transcription factors, usually performed by reelin, is also blocked.


Tissue distribution and expression

VLDLR is found throughout the body, with particularly high expression in fatty acid tissues due to their high level of
triglycerides A triglyceride (from ''wikt:tri-#Prefix, tri-'' and ''glyceride''; also TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids. Triglycerides are the main constituents of body fat in humans and oth ...
, VLDLR’s primary ligand. These tissues include those of the heart, skeletal muscle, and adipose layer. In addition, the receptor is found in macrophages, endothelial cells of capillaries, and in the brain, where it has a very different function from that found in the rest of the body. There is a preferred expression for VLDLR type I in the heart, skeletal muscle and brain, as opposed to type II, which is mainly expressed in non-muscular tissues including the
cerebrum The cerebrum (: cerebra), telencephalon or endbrain is the largest part of the brain, containing the cerebral cortex (of the two cerebral hemispheres) as well as several subcortical structures, including the hippocampus, basal ganglia, and olfac ...
,
cerebellum The cerebellum (: cerebella or cerebellums; Latin for 'little brain') is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as it or eve ...
, kidney, spleen, and aortic endothelial cells. The highest expression of VLDLR is found in the brain. Although VLDLR is found in almost all regions of the brain, its highest expression is restricted to the cortex and cerebellum. Here, the receptor can be found on resting or activated
microglia Microglia are a type of glia, glial cell located throughout the brain and spinal cord of the central nervous system (CNS). Microglia account for about around 5–10% of cells found within the brain. As the resident macrophage cells, they act as t ...
that are associated with
senile plaques Amyloid plaques (also known as neuritic plaques, amyloid beta plaques or senile plaques) are extracellular deposits of amyloid beta (Aβ) protein that present mainly in the grey matter of the brain. Degeneration (medical), Degenerative neuronal ...
and cortical neurons,
neuroblast In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as ''Drosophila,'' neuroblasts are neural progenitor cells ...
s, matrix cells, Cajal-Retzius cells,
glioblast A glioblast is a type of cell located in the embryonic neuroectoderm that has the ability to differentiate into several different types of neuroglia through asymmetric cell division. It comes from a precursor ( spongioblast). However, the latter m ...
s,
astrocytes Astrocytes (from Ancient Greek , , "star" and , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of end ...
,
oligodendrocytes Oligodendrocytes (), also known as oligodendroglia, are a type of neuroglia whose main function is to provide the myelin sheath to neuronal axons in the central nervous system (CNS). Myelination gives metabolic support to, and insulates the axon ...
, and region-specific
pyramidal neurons Pyramidal cells, or pyramidal neurons, are a type of multipolar neuron found in areas of the brain including the cerebral cortex, the hippocampus, and the amygdala. Pyramidal cells are the primary excitation units of the mammalian prefrontal cort ...
. Despite its major role in cholesterol and fatty acid metabolism, VLDLR is not found in the liver. This phenomenon is mainly attributed to the very high levels of LDLR in these areas. In addition, it has been uncovered that this receptor is found, sub-cellularly, in the non-
lipid raft The cell membrane, plasma membranes of cells contain combinations of glycosphingolipids, cholesterol and protein Receptor (biochemistry), receptors organized in glycolipoprotein lipid microdomains termed lipid rafts. Their existence in cellular me ...
sections of cell membranes.


Regulation

Unlike LDLR, VLDLR does not exhibit any feedback mechanism, and hence intracellular
lipoproteins A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, sur ...
are incapable of regulating it. This phenomenon is due to a difference in the
sterol A sterol is any organic compound with a Skeletal formula, skeleton closely related to Cholestanol, cholestan-3-ol. The simplest sterol is gonan-3-ol, which has a formula of , and is derived from that of gonane by replacement of a hydrogen atom on ...
regulatory element-1 (SRE-1) of VLDLR. Normal SRE-1 sequences, like those found in LDLR, are characterized by two repeats of the codon CAC separated by two intervening C nucleotides (5’-CACCCCAC-3’). The
sterol regulatory element-binding protein Sterol regulatory element-binding proteins (SREBPs) are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. Mammalian SREBPs are encoded by the genes ''SREBF1'' and ''SREBF2''. SREBPs belong to the basic-hel ...
-1 (SREBP-1), a
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
, targets the CAC repeats of SRE-1 to regulate the protein’s transcription. However, the ''VLDLR'' gene is encoded by two SRE-1-like sequences that contain
single nucleotide polymorphisms In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...
. These polymorphisms disrupt the SREBP-1 binding to the CAC repeats, and hence eliminate the feedback mechanism seen in other proteins. VLDLR expression is regulated by peroxisome proliferator-activated receptor-gamma (PPAR-γ). A 2010 study showed that the prescription drug
Pioglitazone Pioglitazone, sold under the brand name Actos among others, is an anti-diabetic medication used to treat type 2 diabetes. It may be used with metformin, a sulfonylurea, or insulin. Use is recommended together with exercise and diet. It is not ...
, an
agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
of PPAR-γ, increases VLDLR mRNA expression and protein levels in experiments using mouse fibroblasts. The Pioglitazone treated mice exhibited a higher conversion rate of plasma
triglycerides A triglyceride (from ''wikt:tri-#Prefix, tri-'' and ''glyceride''; also TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids. Triglycerides are the main constituents of body fat in humans and oth ...
into epididymal fats. As expected, mice deficient in VLDLR did not show this same response. These results suggest that VLDLR is important in fat accumulation. Many other hormones and dietary factors also regulate VLDLR expression.
Thyroid hormone File:Thyroid_system.svg, upright=1.5, The thyroid system of the thyroid hormones triiodothyronine, T3 and T4 rect 376 268 820 433 Thyroid-stimulating hormone rect 411 200 849 266 Thyrotropin-releasing hormone rect 297 168 502 200 Hypothalamus r ...
positively regulates VLDLR expression in skeletal muscles of rats, but not in adipose or heart tissues. In rabbits, VLDLR expression in heart muscle is up-regulated by estrogen and down-regulated by granulocyte-macrophage colony-stimulating factor. In
trophoblast The trophoblast (from Greek language, Greek : to feed; and : germinator) is the outer layer of cells of the blastocyst. Trophoblasts are present four days after Human fertilization, fertilization in humans. They provide nutrients to the embryo an ...
-derived cell lines, up-regulated VLDLR expression occurs when cells are incubated with
hypolipidemic agent Lipid-lowering agents, also sometimes referred to as hypolipidemic agents, cholesterol-lowering drugs, or antihyperlipidemic agents are a diverse group of pharmaceuticals that are used to lower the level of lipids and lipoproteins, such as choleste ...
s such as
insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
and
clofibrate Clofibrate (trade name Atromid-S) is a lipid-lowering agent used for controlling the high cholesterol and triacylglyceride level in the blood. It belongs to the class of fibrates. It increases lipoprotein lipase activity to promote the conversion ...
. In contrast,
8-bromoadenosine 3',5'-cyclic monophosphate 8-Bromoadenosine 3',5'-cyclic adenosine monophosphate (8-Br-cAMP) is a brominated derivative of cyclic adenosine monophosphate (cAMP). 8-Br-cAMP is an activator of cyclic AMP-dependent protein kinase, and it is long-acting because it is resistan ...
(8-bromo-cAMP) down-regulates VLDLR expression. Finally, VLDLR is affected by the presence of
apoE Apolipoprotein E (Apo-E) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular diseases. It is encoded in humans by the gene ''APOE''. Apo-E belongs to a family ...
and LDLR. The presence of apoE is required for VLDLR expression regulation, while the absence of LDLR alters the
sterol A sterol is any organic compound with a Skeletal formula, skeleton closely related to Cholestanol, cholestan-3-ol. The simplest sterol is gonan-3-ol, which has a formula of , and is derived from that of gonane by replacement of a hydrogen atom on ...
-regulatory-element-1-like sequences of VLDLR to make them functional in only heart and skeletal muscle.


Function


Beyond the nervous system

VLDLR is a peripheral
lipoprotein A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, sur ...
receptor that functions in lipoprotein metabolism, cardiac
fatty acid In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an ...
metabolism, and fat deposition. In effect, VLDLR will allow
cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...
to reach tissues from the bloodstream, where it may be used in cellular membranes. In addition, it will allow fatty acids to get into cells where they may be used as an energy source. Overall, VLDLR primarily modulates the extra-
hepatic The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
metabolism of
triglyceride A triglyceride (from '' tri-'' and '' glyceride''; also TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids. Triglycerides are the main constituents of body fat in humans and other vertebrates ...
-rich lipoproteins.


Lipoprotein uptake

VLDLR only plays a discrete role in lipid metabolism, but is more significant in stressed situations. Mice with double knockouts in ''VLDLR'' and '' LDLR'' have higher serum
triglyceride A triglyceride (from '' tri-'' and '' glyceride''; also TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids. Triglycerides are the main constituents of body fat in humans and other vertebrates ...
levels than those with only a knockout in the ''LDLR'' gene. In addition, ''LDLR'' knockout mice overexpressing VLDLR have decreased serum triglyceride levels. Although fat deposition is close to normal without VLDLR, its role gains importance when LDLR is deficient. Despite this knowledge on its role in lipoprotein uptake, the complete mechanism of lipid metabolism performed by VLDLR is not fully understood.


= Endocytosis

= VLDLR is known to employ
endocytosis Endocytosis is a cellular process in which Chemical substance, substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a Vesicle (biology and chem ...
, although the exact mechanism of this process is unknown for this protein. Endocytosis is mediated through NPxY sequences known to signal for receptor internalization through clathrin-coated pits. The presence of this sequence in the cytoplasmic tail of VLDLR makes endocytosis possible. In general,
lipoprotein A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, sur ...
receptors undergo a process by which they are endocytosed with their ligand into clathrin-coated pits. From here, they are together transported to early and late
endosomes Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of the endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membra ...
until reaching the
lysosome A lysosome () is a membrane-bound organelle that is found in all mammalian cells, with the exception of red blood cells (erythrocytes). There are normally hundreds of lysosomes in the cytosol, where they function as the cell’s degradation cent ...
. At this point, hydrolysis occurs and lipoprotein is released into the cytoplasm while the receptors are recycled back to the cell surface. It is not yet confirmed if VLDLR follows this exact mechanism, but one closely related to it is likely.


In the nervous system

In addition to its role throughout the body, VLDLR has a unique role in the brain. It is a key component of the
reelin Reelin, encoded by the ''RELN'' gene, is a large secreted extracellular matrix glycoprotein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell–cell interactions. Besides this importa ...
pathway, which functions on one hand side in
neuronal migration The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The field ...
during the development of the brain, on the other hand in the retention of new memory traces in the
hippocampal formation The hippocampal formation is a compound structure in the medial temporal lobe of the brain. It forms a c-shaped bulge on the floor of the inferior horn of the lateral ventricle. Typically, the hippocampal formation is said to included the dent ...
. VLDLR links the reelin protein to an intracellular signaling protein,
Dab1 The Disabled-1 (Dab1) gene encodes a key regulator of Reelin signaling. Reelin is a large glycoprotein secreted by neurons of the developing brain, particularly Cajal-Retzius cells. DAB1 functions downstream of Reln in a signaling pathway that c ...
, that tells the individual neurons where to go within the anatomy of the brain. Mutations in VLDLR often do not lead to major disorganization as seen in reelin mutations. However, a VLDLR mutation does lead to some disorganization primarily located in the
cerebellum The cerebellum (: cerebella or cerebellums; Latin for 'little brain') is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as it or eve ...
, where VLDLR is believed to be most prominent.


Neuronal migration

VLDLR is expressed on migrating neurons to help guide them to their proper location in the brain. This process is part of the
reelin Reelin, encoded by the ''RELN'' gene, is a large secreted extracellular matrix glycoprotein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell–cell interactions. Besides this importa ...
pathway, which is responsible for the inside-out formation of the six-layered
neocortex The neocortex, also called the neopallium, isocortex, or the six-layered cortex, is a set of layers of the mammalian cerebral cortex involved in higher-order brain functions such as sensory perception, cognition, generation of motor commands, ...
. Despite the discovery of this pathway, many of the specifics and molecular mechanisms of this process are still being debated. The presence of two reelin receptors, VLDLR and
ApoER2 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 lipopr ...
, has made it difficult to distinguish each protein’s specific function. VLDLR is primarily responsible for the correct layering of
pyramidal cells Pyramidal cells, or pyramidal neurons, are a type of multipolar neuron found in areas of the brain including the cerebral cortex, the hippocampus, and the amygdala. Pyramidal cells are the primary excitation units of the mammalian prefrontal cort ...
into layer 1 of the
cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. It is the largest site of Neuron, neural integration in the central nervous system, and plays ...
. In particular, the absence of VLDLR may lead to ectopic accumulation of pyramidal cells in this region. VLDLR does not affect the migration of early born cells into an organized layer, but since its absence results in the invasion of these neuroblasts into the marginal zone, it is theorized that VLDLR may encode a “stop signal.” This is supported by the fact that VLDLR is primarily expressed in the cortical plate adjacent to reelin-expressing cells,
Cajal–Retzius cell Cajal–Retzius cells (CR cells) (also known as horizontal cells of Cajal) are a heterogeneous population of morphologically and molecularly distinct reelin-producing cells. They are found in the marginal zone/layer I of the developing cerebral c ...
s, and in the intermediate zone. However, definitive evidence has not yet been found. In general, reelin binds VLDLR and undergoes
endocytosis Endocytosis is a cellular process in which Chemical substance, substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a Vesicle (biology and chem ...
via
clathrin-coated vesicles Clathrin is a protein that plays a role in the formation of coated vesicles. Clathrin was first isolated by Barbara Pearse in 1976. It forms a triskelion shape composed of three clathrin heavy chains and three light chains. When the triskeli ...
. Meanwhile, an intracellular protein,
Dab1 The Disabled-1 (Dab1) gene encodes a key regulator of Reelin signaling. Reelin is a large glycoprotein secreted by neurons of the developing brain, particularly Cajal-Retzius cells. DAB1 functions downstream of Reln in a signaling pathway that c ...
, has a PI/PTB domain that interacts with the NPxY sequence found in the cytoplasmic tail of VLDLR. As a result, Dab1 is tyrosine phosphorylated and reelin is degraded. Finally, phosphorylated Dab1 activates an intracellular signaling cascade that directs neuroblasts to their proper location through the alteration of the
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...
. Many of the specifics of this pathway are still being investigated. It is not yet known if Dab1 is phosphorylated as a result of the endocytosis of reelin, or if there is another mechanism at play. In addition to the organization of the neocortex, VLDLR also plays a role in neuronal migration of the
hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...
and the
Purkinje cells Purkinje cells or Purkinje neurons, named for Czech physiologist Jan Evangelista Purkyně who identified them in 1837, are a unique type of prominent, large neuron located in the cerebellar cortex of the brain. With their flask-shaped cell bo ...
of the
cerebellum The cerebellum (: cerebella or cerebellums; Latin for 'little brain') is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as it or eve ...
. Yet, much information on this process is still unknown.


Associated disorders

Mutations within the ''VLDLR'' gene lead to a multitude of disorders of varying severities. These disorders are usually associated with
cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...
homeostasis In biology, homeostasis (British English, British also homoeostasis; ) is the state of steady internal physics, physical and chemistry, chemical conditions maintained by organism, living systems. This is the condition of optimal functioning fo ...
or a disorganization of neuron ordering in the brain due to disruption of the
reelin Reelin, encoded by the ''RELN'' gene, is a large secreted extracellular matrix glycoprotein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell–cell interactions. Besides this importa ...
pathway. The most prominent of these diseases are type I
lissencephaly Lissencephaly (, meaning 'smooth brain') is a set of rare brain disorders whereby the whole or parts of the surface of the brain are smooth. It is caused by defective neuronal migration during the 12th to 24th weeks of gestation, resulting in a ...
, VLDR-associated
cerebellar hypoplasia Cerebellar hypoplasia is characterized by reduced cerebellar volume, even though cerebellar shape is (near) normal. It consists of a heterogeneous group of disorders of cerebellum, cerebellar maldevelopment presenting as early-onset Non-progress ...
, and
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
. In contrast to causing diseases, VLDLR has also been identified as a possible remedy for some disorders. Implementation of VLDLR into the liver may cure
familial hypercholesterolemia Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein cholesterol (LDL cholesterol), in the blood and early cardiovascular diseases. The mos ...
(FH) in patients who either have defective LDLR or have defective immune systems that attack this protein. Since VLDLR is non-immunogenic it does not initiate an immune response, thus it is able to function normally under defective immune systems. In addition, being that
apoE Apolipoprotein E (Apo-E) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular diseases. It is encoded in humans by the gene ''APOE''. Apo-E belongs to a family ...
, a major ligand of VLDLR, is a leading genetic risk factor for
Alzheimer’s disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
, VLDLR may play a role in modulating the risk of this disorder which is explained by the fact that a decrease in reelin signaling in the fascia dentata is supposed to initiate Alzheimer's disease. VLDLR has also been shown to reduce the chances of premature heart disease and stroke because VLDLR clears out lipoprotein A (Lp(a)), a major inherited risk factor for these diseases.


Type 1 lissencephaly

Type I
lissencephaly Lissencephaly (, meaning 'smooth brain') is a set of rare brain disorders whereby the whole or parts of the surface of the brain are smooth. It is caused by defective neuronal migration during the 12th to 24th weeks of gestation, resulting in a ...
, or agyria-pachygyria, is a rare developmental disorder characterized by the absence of
gyri In neuroanatomy, a gyrus (: gyri) is a ridge on the cerebral cortex. It is generally surrounded by one or more sulcus (neuroanatomy), sulci (depressions or furrows; : sulcus). Gyri and sulci create the folded appearance of the brain in huma ...
and
sulci Sulci or Sulki (in Greek , Stephanus of Byzantium, Steph. B., Ptolemy, Ptol.; , Strabo; , Pausanias (geographer), Paus.), was one of the most considerable cities of ancient Sardinia, situated in the southwest corner of the island, on a small isla ...
in the brain. These severe malformations are a result of aberrant
neuronal migration The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The field ...
. In classical type I lissencephaly, neuronal migration begins but is unable to continue to completion. This process is likely disrupted by alterations to several genes, including the ''VLDLR'', '' DCX'', '' ARX'', ''
TUBA1A Tubulin alpha-1A chain is a protein that in humans is encoded by the ''TUBA1A'' gene. Tubulin alpha-1A chain is a type of alpha-tubulin involved in the formation of microtubules, which are structural proteins that play a role in the cytoskeletal ...
'', ''
RELN Reelin, encoded by the ''RELN'' gene, is a large secreted extracellular matrix glycoprotein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell–cell interactions. Besides this impor ...
'' and ''
LIS1 Platelet-activating factor acetylhydrolase IB subunit alpha or Lisencephaly protein-1 (LIS-1) is an enzyme that in humans is encoded by the ''PAFAH1B1'' gene. The protein plays an important role in regulating the motor protein dynein. Function ...
''. The severity of type I lissencephaly therefore varies with the mutation type. A homozygous deletion affecting the ''VLDLR'' gene results in a low degree of cortical thickening and absence of a cell-sparse zone. The cell-sparse zone describes the region between the outer and inner cortical layers of arrested neurons. In addition, type 1 lissencephaly is closely associated with
cerebellar hypoplasia Cerebellar hypoplasia is characterized by reduced cerebellar volume, even though cerebellar shape is (near) normal. It consists of a heterogeneous group of disorders of cerebellum, cerebellar maldevelopment presenting as early-onset Non-progress ...
.


VLDLR-associated cerebellar hypoplasia

Disequilibrium syndrome (DES) was first described in the 1970s as a non-progressive, neurological disorder. In a 2005 study, DES was renamed as VLDLR-associated cerebellar hypoplasia (VLDLRCH) after its cause was linked to a disruption in the ''VLDLR'' gene. At least six mutations affecting the homozygous recessive allele of the ''VLDLR'' gene have been identified and found to cause VLDLRCH. Several of these mutations have been localized to specific
exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...
s encoding the gene. One such mutation is a
cytosine Cytosine () (symbol C or Cyt) is one of the four nucleotide bases found in DNA and RNA, along with adenine, guanine, and thymine ( uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attac ...
to
thymine Thymine () (symbol T or Thy) is one of the four nucleotide bases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidine ...
transition at base pair 1342 in exon 10 that causes a substitution at Arg448 for a termination signal. Likewise, there is evidence of a cytosine to thymine transition at base pair number 769 in exon 5 that causes a substitution at Arg257 for a termination signal. A third known mutation is caused by a homozygous 1-base pair deletion in exon 17 that causes a frameshift and premature termination in the O-linked sugar domain. All such alterations to the ''VLDLR'' gene prevent the production of VLDLR and are therefore termed loss-of-function mutations. The recognized symptoms of VLDLRCH are moderate-to-severe intellectual disability, seizures,
dysarthria Dysarthria is a speech sound disorder resulting from neurological injury of the motor component of the motor–speech system and is characterized by poor articulation of phonemes. It is a condition in which problems effectively occur with the ...
,
strabismus Strabismus is an eye disorder in which the eyes do not properly align with each other when looking at an object. The eye that is pointed at an object can alternate. The condition may be present occasionally or constantly. If present during a ...
and delayed locomotion. In some cases, children with VLDLRCH learn to walk very late in development after the age of six years, or never learn to walk independently. The frequency of this disorder is unknown because early diagnosis of VLDLRCH is difficult using imaging techniques. It is associated with parental
consanguinity Consanguinity (from Latin '':wikt: consanguinitas, consanguinitas'' 'blood relationship') is the characteristic of having a kinship with a relative who is descended from a common ancestor. Many jurisdictions have laws prohibiting people who are ...
and found in secluded communities such as the
Hutterite Hutterites (; ), also called Hutterian Brethren (German: ), are a communal ethnoreligious branch of Anabaptists, who, like the Amish and Mennonites, trace their roots to the Radical Reformation of the early 16th century and have formed intent ...
s and inbred families from Iran and Turkey.


Atherosclerosis

Atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
is marked by an excessive accumulation of
cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...
by
macrophages Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
, leading to their transformation into foam cells. This accumulation of cholesterol is caused by dysregulation of cholesterol influx and efflux. Since macrophages do not have the ability to limit the influx of cholesterol, the balance is completely dependent on efflux pathways. VLDLR is expressed by macrophages, and functions in the uptake of native
lipoproteins A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, sur ...
. Uniquely, VLDLR does not respond to cholesterol loading, likely due to its lack of feedback mechanisms. The inability to control its uptake of native lipoproteins makes VLDLR a pro-atherogenic factor. This characteristic is supported by results from a 2005 study, in which reintroduction of VLDLR into ''VLDLR'' knockout mice led to greatly increased atherosclerotic lesion development.


See also

*
LDL receptor The low-density lipoprotein receptor (LDL-R) is a mosaic protein of 839 amino acids (after removal of 21-amino acid signal peptide) that mediates the endocytosis of cholesterol-rich low-density lipoprotein (LDL). It is a cell-surface receptor ...
*
Very low-density lipoprotein Very-low-density lipoprotein (VLDL), density relative to extracellular water, is a type of lipoprotein made by the liver. VLDL is one of the five major groups of lipoproteins (chylomicrons, VLDL, intermediate-density lipoprotein, LDL, low-density ...


References


Further reading

* * * * * * * * * * * * * * * * * *


External links


GeneReviews/NCBI/NIH/UW entry on VLDLR-Associated Cerebellar Hypoplasia or Dysequilibrium Syndrome-VLDLR
* {{DEFAULTSORT:Vldl Receptor Low-density lipoprotein receptor gene family