Apolipoprotein D

Last updated
APOD
Protein APOD PDB 2APD.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases APOD , Apod, apolipoprotein D
External IDs OMIM: 107740 MGI: 88056 HomoloGene: 1246 GeneCards: APOD
Orthologs
SpeciesHumanMouse
Entrez

347

11815

Ensembl

ENSG00000189058

ENSMUSG00000022548

UniProt

P05090

P51910

RefSeq (mRNA)

NM_001647

NM_001301353
NM_001301354
NM_007470

RefSeq (protein)

NP_001638

NP_001288282
NP_001288283
NP_031496

Location (UCSC) Chr 3: 195.57 – 195.58 Mb Chr 16: 31.12 – 31.13 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Apolipoprotein D (ApoD) is a protein that in humans is encoded by the APOD gene. [5] [6] [7] Unlike other lipoproteins, which are mainly produced in the liver, apolipoprotein D is mainly produced in the brain and testes. [8] It is a 29 kDa glycoprotein discovered in 1963 as a component of the high-density lipoprotein (HDL) fraction of human plasma. [9] [10] It is the major component of human mammary cyst fluid. The human gene encoding it was cloned in 1986 and the deduced protein sequence revealed that ApoD is a member of the lipocalin family, small hydrophobic molecule transporters. [6] ApoD is 169 amino acids long, including a secretion peptide signal of 20 amino acids. It contains two glycosylation sites (aspargines 45 and 78) and the molecular weight of the mature protein varies from 20 to 32 kDa (see figure 1).

Contents

Rassart Figure 1 Rassart Figure 1.jpg
Rassart Figure 1

The resolved tertiary structure shows that ApoD is composed of 8 anti-parallel β-strands forming a hydrophobic cavity capable of receiving different ligands. [11] [12] ApoD also contains 5 cysteine residues, 4 of which are involved in intra-molecular disulfide bonds.

Function

Apolipoprotein D (ApoD) is a component of HDL that has no marked similarity to other apolipoprotein sequences. It has a high degree of homology to plasma retinol-binding protein and other members of the alpha 2 microglobulin protein superfamily of carrier proteins, also known as lipocalins. It is a glycoprotein of estimated molecular weight 33 KDa. Apo-D is closely associated with the enzyme lecithin-cholesterol acyltransferase (LCAT) - an enzyme involved in lipoprotein metabolism. [7] ApoD has also been shown to be an important link in the transient interaction between HDL and low-density lipoprotein (LDL) particles and between HDL particles and cells. [13]

Interactions and ligands

ApoD was shown to bind steroid hormones such as progesterone and pregnenolone with a relatively strong affinity, and to estrogens with a weaker affinity. [14] [15] Molecular modeling studies identified bilirubin, a breakdown product of heme, as a potential ligand. [11] Arachidonic acid (AA) was identified as an ApoD ligand with a much better affinity than that of progesterone or pregnenolone. [16] AA is the precursor of prostaglandins and leukotrienes, molecules that are involved in inflammation, platelet aggregation and cellular regulation. [17] A very poor binding between ApoD and cholesterol has also been observed. [18] Other ApoD ligands include E-3-methyl-2-hexenoïc acid, a scent molecule present in body odor secretions; [19] retinoic acid, which is involved in cellular differentiation; and sphingomyelin and sphingolipids, which are major components of HDL and cell membranes. [20] The fact that apoD may bind such a large variety of ligands strongly support the hypothesis that it could be a multi-ligand, multi-functional protein.

Clinical significance

APOD is a biomarker of androgen insensitivity syndrome (AIS). APOD is an androgen up-regulated gene in normal scrotal fibroblast cells in comparison to labia majora cells in females with complete AIS (CAIS). [21] APOD is associated with neurological disorders and nerve injury, especially related to myelin sheath. APOD was shown to be elevated in a rat model of stroke. [8] APOD is elevated in patients with schizophrenia, bipolar disorder, and Alzheimer's disease. [8]

ApoD expression in cells and tissues

Analysis of the ApoD gene promoter region identified a large number of promoter regulatory elements, among which response elements to steroids, estrogen, progesterone, and glucocorticoids. Response elements to fatty acids, acute phase proteins, serum. and to the immune factor NF-κB were also observed. [22] [23] [24] The presence of such a large number of regulatory sequences suggests that the regulation of its expression is very complex.

ApoD has been identified in 6 mammalian species as well as in chickens, [25] [26] fruit flies, [27] plants [28] and bacteria. [29] In humans, monkeys, rabbits and guinea pigs, ApoD is highly expressed in the nervous system (brain, cerebellum, and peripheral nerves). Otherwise, expression levels of ApoD vary largely from organ to organ and species to species, with humans displaying the most diverse expression of ApoD, and mice and rats almost exclusively expressing ApoD in the nervous system (see Figure 2).

Rassart Figure 2 Rassart Figure 2.jpg
Rassart Figure 2

ApoD concentration in human plasma varies between 5 and 23 mg/100 ml. [30] In the nervous system, the ApoD mRNA is expressed by fibroblasts, astrocytes and oligodendrocytes [31] [32] [33] As a glycoprotein with a peptide signal, ApoD is secreted. Yet it can also be actively reinternalized. The transmembrane glycoprotein Basigin (BSG; CD147) was identified as an ApoD receptor. [34] BSG is a membrane glycoprotein receptor, member of the immunoglobulin family, involved in several pathologies such as cancer and Alzheimer's disease. [35]

Modulation of ApoD expression

Studies on several cell types have shown that ApoD expression can be induced by several stressing situations such as growth arrest, senescence, oxidative and inflammatory stresses. [23] [24] ApoD expression is also increased in several neuropathologies. ApoD expression is modulated in several pathologies such as HDL familial deficiency, Tangier disease, [36] [37] LCAT familial deficit [38] and type 2 diabetes. [39] It is overexpressed in numerous cancers, [40] including breast, [41] [42] ovary, prostate, [43] skin [44] [45] and central nervous system (CNS) cancer. In many cases, its expression is correlated with highly differentiated, non-invasive and non-metastatic state.

A role in lipid metabolism has been identified for ApoD by a study on transgenic (Tg) mice overexpressing human ApoD in the CNS. [46] These mice slowly develop a hepatic and muscular steatosis accompanied with insulin resistance. However, none of the Tg mice develop obesity nor diabetes. ApoD induced lipid accumulation is not due to de novo lipogenesis but rather from increased lipid uptake in response to prostaglandin overproduction. [47]

Plasma ApoD levels decrease significantly during normal uncomplicated pregnancy. ApoD is further decreased in women with excessive gestational weight gain and their newborns. In these women, the ApoD concentration was tightly associated with the lipid parameters. [48] In morbidly obese women (BMI over 40) adipose tissues, ApoD protein expression is positively correlated with parameters of metabolic health. ApoD-null female mice (mice in which the ApoD gene was inactivated) present progressive (up to 50%) bone volume reduction with aging. [49]

ApoD and the nervous system

Both ApoD and Apolipoprotein E (ApoE) protein levels increase drastically at the site of regeneration following a nerve crush injury in the rat. [50] [51] Similar observations have been made in rabbits, marmoset monkeys and in mice. [52] Elevated levels of ApoD were observed in the cerebrospinal fluid, hippocampus and cortex of human patients with Alzheimer's disease, cerebrovascular disease, motoneuron disease, meningoencephalitis and stroke. [53] ApoD expression is altered in plasma and post-mortem brains of patients with schizophrenia. [54] In patients with Parkinson's disease or with multiple sclerosis, ApoD expression is strongly increased in glial cells of the substantia nigra. [55] [56]

Niemann-Pick type C (NPC) is a genetic disorder affecting cholesterol transport that is accompanied by chronic progressive neurodegeneration. In animal models of NPC, ApoD expression is increased in the plasma and the brain. [57] In rats, ApoD expression increases in the hippocampus after enthorinal cortex lesioning. ApoD mRNA and protein increases in the ipsilateral region of hippocampus as early as 2 days post-lesion (DPL), remains high for 10 days and returns to normal after 14 DPL, a period considered necessary for a complete reinervation. [58] Similar results are obtained after injection of kainic acid, an analog of glutamic acid which causes a severe neurodegenerative injury in the hippocampus [59] or after experimentally-induced stoke. [60] [61] ApoD expression is also increased in the aging brain. [53] Altogether, these data suggest that ApoD plays an important role in neural preservation and protection.

Tg mice are less sensitive to oxidative stress induced by paraquat, a free oxygen radical generator, and present reduced lipid peroxidation levels. In contrast, apoD-null mice show increased sensitivity to oxidative stress, increased brain lipid peroxidation and impaired locomotor and learning abilities. Similar results have been observed in a drosophila model. [62] Mice infected with the human coronavirus OC43 develop encephalitis and inflammatory demyelination of the CNS, a disease very similar to multiple sclerosis. Tg mice infected with OC43 display increased survivability compared to control animals. [63] Tg mice treated with kainic acid show a significant reduction of inflammatory responses and a much stronger protection against apoptosis in the hippocampus than control animals. [64] ApoD-null mice crossed with APP-PS1 mice, a mouse model of Alzheimer's disease, displayed a 2-fold increase of hippocampal amyloid plaque load. In contrast, the progeny of Tg mice crossed with APP-PS1 mice displayed reduced hippocampal plaque load by 35%, and a 35% to 65% reduction of amyloid peptide levels. [65]

Notes

Related Research Articles

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 that enable fats and cholesterol to move within the water-based solution of the bloodstream. VLDL is assembled in the liver from triglycerides, cholesterol, and apolipoproteins. VLDL is converted in the bloodstream to low-density lipoprotein (LDL) and intermediate-density lipoprotein (IDL). VLDL particles have a diameter of 30–80 nm. VLDL transports endogenous products, whereas chylomicrons transport exogenous (dietary) products. In the early 2010s both the lipid composition and protein composition of this lipoprotein were characterised in great detail.

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

Lipoprotein lipase (LPL) (EC 3.1.1.34, systematic name triacylglycerol acylhydrolase (lipoprotein-dependent)) is a member of the lipase gene family, which includes pancreatic lipase, hepatic lipase, and endothelial lipase. It is a water-soluble enzyme that hydrolyzes triglycerides in lipoproteins, such as those found in chylomicrons and very low-density lipoproteins (VLDL), into two free fatty acids and one monoacylglycerol molecule:

<span class="mw-page-title-main">Apolipoprotein</span> Proteins that bind lipids to transport them in body fluids

Apolipoproteins are proteins that bind lipids to form lipoproteins. They transport lipids in blood, cerebrospinal fluid and lymph.

<span class="mw-page-title-main">Apolipoprotein E</span> Cholesterol-transporting protein most notably implicated in Alzheimers disease

Apolipoprotein E (Apo-E) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in the Alzheimer's disease and cardiovascular diseases. It is encoded in humans by the gene APOE.

<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">Apolipoprotein C-II</span> Protein-coding gene in the species Homo sapiens

Apolipoprotein C-II, or apolipoprotein C2 is a protein that in humans is encoded by the APOC2 gene.

<span class="mw-page-title-main">Cholesterol 7 alpha-hydroxylase</span> Protein-coding gene in the species Homo sapiens

Cholesterol 7 alpha-hydroxylase also known as cholesterol 7-alpha-monooxygenase or cytochrome P450 7A1 (CYP7A1) is an enzyme that in humans is encoded by the CYP7A1 gene which has an important role in cholesterol metabolism. It is a cytochrome P450 enzyme, which belongs to the oxidoreductase class, and converts cholesterol to 7-alpha-hydroxycholesterol, the first and rate limiting step in bile acid synthesis.

<span class="mw-page-title-main">Lipocalin</span>

The lipocalins are a family of proteins which transport small hydrophobic molecules such as steroids, bilins, retinoids, and lipids, and most lipocalins are also able to bind to complexed iron as well as heme. They share limited regions of sequence homology and a common tertiary structure architecture. This is an eight stranded antiparallel beta barrel with a repeated + 1 topology enclosing an internal ligand binding site.

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

Apolipoprotein C-III also known as apo-CIII, and apolipoprotein C3, is a protein that in humans is encoded by the APOC3 gene. Apo-CIII is secreted by the liver as well as the small intestine, and is found on triglyceride-rich lipoproteins such as chylomicrons, very low density lipoprotein (VLDL), and remnant cholesterol.

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

Apolipoprotein C-IV, also known as apolipoprotein C4, is a protein that in humans is encoded by the APOC4 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">Hepatic lipase</span> Mammalian protein found in Homo sapiens

Hepatic lipase (HL), also called hepatic triglyceride lipase (HTGL) or LIPC (for "lipase, hepatic"), is a form of lipase, catalyzing the hydrolysis of triacylglyceride. Hepatic lipase is coded by chromosome 15 and its gene is also often referred to as HTGL or LIPC. Hepatic lipase is expressed mainly in liver cells, known as hepatocytes, and endothelial cells of the liver. The hepatic lipase can either remain attached to the liver or can unbind from the liver endothelial cells and is free to enter the body's circulation system. When bound on the endothelial cells of the liver, it is often found bound to heparan sulfate proteoglycans (HSPG), keeping HL inactive and unable to bind to HDL (high-density lipoprotein) or IDL (intermediate-density lipoprotein). When it is free in the bloodstream, however, it is found associated with HDL to maintain it inactive. This is because the triacylglycerides in HDL serve as a substrate, but the lipoprotein contains proteins around the triacylglycerides that can prevent the triacylglycerides from being broken down by HL.

<span class="mw-page-title-main">APOA5</span> Protein-coding gene in the species Homo sapiens

Apolipoprotein A-V is a protein that in humans is encoded by the APOA5 gene on chromosome 11. It is significantly expressed in liver. The protein encoded by this gene is an apolipoprotein and an important determinant of plasma triglyceride levels, a major risk factor for coronary artery disease. It is a component of several lipoprotein fractions including VLDL, HDL, chylomicrons. It is believed that apoA-V affects lipoprotein metabolism by interacting with LDL-R gene family receptors. Considering its association with lipoprotein levels, APOA5 is implicated in metabolic syndrome. The APOA5 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

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

Apolipoprotein A-II is a protein that in humans is encoded by the APOA2 gene. It is the second most abundant protein of the high density lipoprotein particles. The protein is found in plasma as a monomer, homodimer, or heterodimer with apolipoprotein D. ApoA-II regulates many steps in HDL metabolism, and its role in coronary heart disease is unclear. Remarkably, defects in this gene may result in apolipoprotein A-II deficiency or hypercholesterolemia.

<span class="mw-page-title-main">APOA4</span> Protein-coding gene in the species Homo sapiens

Apolipoprotein A-IV is plasma protein that is the product of the human gene APOA4.

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

Phospholipid transfer protein is a protein that in humans is encoded by the PLTP gene.

<span class="mw-page-title-main">Serum amyloid A1</span> Protein-coding gene in the species Homo sapiens

Serum amyloid A1 (SAA1) is a protein that in humans is encoded by the SAA1 gene. SAA1 is a major acute-phase protein mainly produced by hepatocytes in response to infection, tissue injury and malignancy. When released into blood circulation, SAA1 is present as an apolipoprotein associated with high-density lipoprotein (HDL). SAA1 is a major precursor of amyloid A (AA), the deposit of which leads to inflammatory amyloidosis.

<span class="mw-page-title-main">GPLD1</span> Protein-coding gene in the species Homo sapiens

Phosphatidylinositol-glycan-specific phospholipase D is an enzyme that in humans is encoded by the GPLD1 gene.

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

Apolipoprotein M is an apolipoprotein and member of the lipocalin protein family that in humans is encoded by the APOM gene. It is found associated with high density lipoproteins and to a lesser extent with low density lipoproteins and triglyceride-rich lipoproteins. The encoded protein is secreted through the plasma membrane but remains membrane-bound, where it is involved in lipid transport. Two transcript variants encoding two different isoforms have been found for this gene, but only one of them has been fully characterized. It lacks an external amphipathic motif and is uniquely secreted to plasma without cleavage of its terminal signal peptide. The average molecular weight is 21253 Da, and the monoisotopic molecular weight is 21239 Da.

<span class="mw-page-title-main">ABCA7</span> Protein-coding gene in the species Homo sapiens

ATP-binding cassette sub-family A member 7 is a protein that in humans is encoded by the ABCA7 gene.

References

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