VLDL receptor

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.

VLDLR is a member of the low density lipoprotein (LDL) receptor family, which is entirely composed of type I transmembrane lipoprotein receptors. All members of this family share five highly conserved structural domains: an extracellular N terminal ligand binding domain with cysteine rich repeats (also called ligand binding repeats), an epidermal growth factor (EGF), an O linked glycosylation 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. 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 residues that constitute the signal peptide. 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. 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.

Receptor associated protein (RAP) and thrombospondin 1 (THBS1) have been identified as compounds that bind VLDLR. In many cases, these compounds exhibit inhibitory effects. THBS1 binds VLDLR and blocks ligand binding.

VLDLR is found throughout the body, with particularly high expression in fatty acid tissues due to their high level of triglycerides, 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, VLDLR links the reelin protein to an intracellular signaling protein, Dab1, 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, where VLDLR is believed to be most prominent. VLDLR is primarily responsible for the correct layering of pyramidal cells into layer 1 of the cerebral cortex. In particular, the absence of VLDLR may lead to ectopic accumulation of pyramidal cells in this region. 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 and the Purkinje cells of the cerebellum. Yet, much information on this process is still unknown. 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. In addition, type 1 lissencephaly is closely associated with 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 exons encoding the gene. One such mutation is a cytosine to thymine 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, strabismus 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 and found in secluded communities such as the Hutterites and inbred families from Iran and Turkey.

Atherosclerosis is marked by an excessive accumulation of cholesterol by macrophages, 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. 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.