Apo lipoproteins structure and function

Name :Eman abd el raouf ahmed

Definition

Apo lipoproteins are the protein components of lipoproteins, the lipid–protein complexes responsible for transporting lipids in the blood. They may have additional specialized functions that are encoded by their genes. This review summarizes the current knowledge on gene and protein structure and the function of this rather complex group of proteins.http://www.els.net/WileyCDA/ElsArticle/refId-

a0005909.html

From genes to proteins Structural organization of the human apolipoprotein (Apo) A‐I, A‐II, A‐IV, C‐I,

C‐II, C‐III and E genes. The wide bars represent the exons and are divided into several regions: the open bars at the two ends represent the 5′ and 3′ untranslated regions; the hatched bars, the signal peptide regions; and the solid bars, the mature peptide regions of the respective genes. The numbers above the exons indicate the length (in nucleotides) of the exons.

THE DISTRIBUTION OF APOLIPOPROTEIN E GENOTYPE

• Apolipoprotein E (ApoE) is encoded by the codominant alleles ε2, ε3, and ε4, resulting in 6 bi-allelic genotypes

• The corresponding protein isoforms differ in their lipoprotein receptor affinity, antioxidant activity, and inflammation modulatory properties

• APOE ε4 carriership is associated with an increased risk of atherosclerosis and dementia

• Approximately 65%–75% of patients with Alzheimer's disease carry the ε4 allele

• http://aje.oxfordjournals.org/content/early/2015/01/21/aje.kwu442

Composition and structure Lipoproteins are complex aggregates of lipids and proteins that render the lipids compatible with the

aqueous environment of body fluids and enable their transport throughout the body of all vertebrates and insects to tissues where they are required.

Lipoproteins are synthesised mainly in the liver and intestines. Within the circulation, these aggregates are in a state of constant flux, changing in composition and physical structure as the peripheral tissues

take up the various components before the remnants return to the liver.

The most abundant lipid constituents are triacylglycerols, free cholesterol, cholesterol esters and phospholipids (phosphatidylcholine and sphingomyelin especially ), though fat-soluble vitamins and anti-

oxidants are also transported in this way.

Free (unesterified) fatty acids and lysophosphatidylcholine are bound to the protein albumin by hydrophobic forces in plasma and in effect are detoxified.

the lipoprotein aggregates should be described in terms of the different protein components or apoproteins (or 'apolipoproteins'), as these determine the overall structures and metabolism, and the

interactions with receptor molecules in liver and peripheral tissues.

the practical methods that have been used to segregate different lipoprotein classes have determined the nomenclature.

Classification the main groups are classified as chylomicrons (CM), very-low-density

lipoproteins (VLDL), low-density lipoproteins (LDL) and high-density lipoproteins (HDL), based on the relative densities of the aggregates on ultracentrifugation.

these classes can be further refined by improved separation procedures, and intermediate-density lipoproteins (IDL) and subdivisions of the HDL (e.g. HDL1, HDL2, HDL3 and so forth) are often defined, and each of these may have distinctive apoprotein compositions and biological properties that are relevant to cardiovascular disease

Density is determined largely by the relative concentrations of triacylglycerolsand proteins and by the diameters of the broadly spherical particles, which vary from about 6000Å in CM to 100Å or less in the smallest HDL. An alternative nomenclature is based on the relative mobilities on electrophoresis on agarosegels. Thus, α, pre-β and β lipoproteins correspond to HDL, VLDL and LDL, respectively.

physical propertiesThe physical properties of apoproteins enable them to bind readily at the interface between water and phospholipids, and specifically they bind to the phospholipids on the surface of the lipoproteins. In effect, this outer shell of amphipathic lipids and proteins solubilizes the hydrophobic lipid core in the aqueous environment. Each apolipoprotein, other than apo B100, tends to have a helical shape with a hydrophobic domain on one side that binds to the lipid core and a hydrophilic face that orientates to the aqueous phase.

http://lipidlibrary.aocs.org/Lipids/lipoprot/index.htm

Physical properties and lipid compositions of lipoprotein classes.

Comment: The fatty acid compositions of the main lipid classes ,As might be expected, the

triacylglycerols tend to contain a high proportion of saturated and monoenoic fatty acids, while the phospholipids contain the highest proportion of polyunsaturated, specifically arachidonate. The cholesterol esters are enriched in linoleate, reflecting their biosynthetic origin .Minor differences only occur for each lipid among the lipoprotein classes. The composition of the triacylglycerols of the chylomicrons depends largely on that of the dietary fatty acids

http://lipidlibrary.aocs.org/Lipids/lipoprot/index.htm

Types according to Molecular weight

structureLipoproteins are spherical (VLDL, LDL, HDL) to discoidal (nascent HDL) in shape with a core of non-polar lipids, triacylglycerols and cholesterol esters, and a surface monolayer, ~20Å thick, consisting of apoproteins, phospholipids and non-esterified cholesterol, which serves to present a hydrophobic face to the aqueous phase

structure

Apo B100 and apo B48 large and water-insoluble and they are the only non-exchangeable apoproteins, which are assembled into triacylglycerol-rich lipoproteins with their lipid components in the intestines or liver. Cholesterol esters are required for proper folding of apo B. With 4536 amino acid residues, apo B100 is one of the largest monomeric proteins known; apo B48 represents the N-terminal 48% of apo B100. These stay with their lipid aggregates during their passage in plasma and the various metabolic changes that occur, until they are eventually removed via specific receptors. The remaining soluble or exchangeable apoproteins, such as apo E, apo A4, apo C3, apo A5, and apo A1, are much smaller in molecular weight and can exchange between lipoprotein classes and acquire lipids during circulation.

Apo A1 is the main protein component of HDL, and is synthesised within the liver

(70%) and intestine (30%). It is a 28-kDa single polypeptide consisting of 243-amino acids, which has no disulfide linkages or glycosylation. Apart from the 44 amino acid N-terminal region, the protein is arranged as eight α-helical segments of 22 amino acids with two 11-mer repeats, and in some instances these are separated by proline residues. It is believed that the helices are amphipathic, each with a hydrophobic face that interacts with lipids and a polar face that interacts with the aqueous phase. The molecule probably exists in several conformational forms.

Apo A2 is the second most important HDL apolipoprotein, and it exists as a homodimer with two polypeptide chains, each 77 amino acids in length and linked by a disulfide bond.

Human apo A4 is the largest member of the exchangeable apolipoproteinfamily and is a 376-amino acid glycoprotein, which is synthesised in intestinal enterocytes and secreted as a constituent of chylomicrons

Apo protein(a) is an Adhesive ProteinThe apo(a) molecule contains the arginine-glycine-aspartate sequence

characteristic of adhesive proteins

Properties such as organ morphogenesis, differentiation, and growth have recently been discovered to be associated with a number of proteins present in the extracellular matrix and the blood, such as fibronectin, collagen, laminin, vitronectin, osteopontin including also coagulation factors such as fibrinogen and von Willebrand factor. These ‘adhesive proteins’ contain a characteristic amino-acid sequence: arginine-glycine-aspartate (RGD), by means of which they interact with integrins, a family of cell surface receptors for adhesive proteins.

Detection of apo(a) in human sperm

o When human sperm was analysed in our laboratory, both the seminal plasma and the cellular fraction were found to contain apo(a).

o We could not detect any apo B associated with this apo(a). The detection of apo(a) in human sperm is the proof that isolated apo(a) is actually produced and secreted into a body fluid independently of apoB and lipoprotein particles.

The role of the adhesive protein apo(a) under pathological conditions

Apo(a) co-ordinates the interaction between cellular systems and the extracellular matrix during repair processes. Apo(a) is involved in tissue reformation during acute repair processes such as wound-healing and Lp(a) plasma levels are known to be elevated during the post operative phase.

Chronic repair processes are characteristic for all pathological states and they are sustained by chronic ascorbate deficiency. In this situation adhesive proteins play a particular role. They interact specifically with cellular systems such as monocytes, T cells as well as thrombocytes and thereby play a critical role in inflammatory, infectious, hemostatic and many other processes

The adhesive protein apo(a), on the basis of its physiological properties, may play an important role in disease containment, tissue reorganisation and chronic repair processes in general. The elevation of Lp(a) plasma levels as established for cancer, cardiovascular, inflammatory and many other diseases is additional confirmation for this concept.

In this context it is noteworthy that apo(a) can interact with a variety of other adhesive proteins, such as fibrinogen, collagen, and fibronectin. The interaction of apo(a) with fibronectin is of particular interest.

Apo(a) and fibrnectin

Fibronectin is one of the best-characterised adhesive proteins. It is present in plasma and other body fluids, with a particularly high concentration in the seminal fluid. Fibronectin is involved in cellular migration during embryogenesis, morphogenesis, differentiation, and growth of many systems. In particular it has been shown to be involved in development and differentiation of the brain and the peripheral nervous system. Other functions comprise platelet aggregation, thrombus formation, and wound healing

Apo(a) and fibronectin share common structural and functional properties. Both molecules consist of numerous repeated segments, including kringle structures, and possibly share common ancestral genes. Both apo(a) and fibronectin can bind to fibrin and collagen. A particularly well-characterised region is the cell-binding region of fibronectin, which contains an RGD sequence and is critically involved in the interaction of fibronectin with integrins and different cell systems.

http://www4.dr-rath-foundation.org/THE_FOUNDATION/About_Dr_Matthias_Rath/publications/pub08.htm

the normal function of the APOB gene

The APOB gene provides instructions for making two versions of the apolipoprotein B protein, a short version called apolipoprotein B-48 and a longer version known as apolipoprotein B-100. Both of these proteins are components of lipoproteins, which are particles that carry fats and fat-like substances (such as cholesterol) in the blood.

Apolipoprotein B-48 is produced in the intestine, where it is a building block of a type of lipoprotein called a chylomicron. As food is digested after a meal, chylomicrons are formed to carry fat and cholesterol from the intestine into the bloodstream. Chylomicrons are also necessary for the absorption of certain fat-soluble vitamins such as vitamin E and vitamin A.

Apolipoprotein B-100, which is produced in the liver, is a component of several other types of lipoproteins. Specifically, this protein is a building block of very low-density lipoproteins (VLDLs), intermediate-density lipoproteins (IDLs), and low-density lipoproteins (LDLs). These related molecules all transport fats and cholesterol in the bloodstream.

Low-density lipoproteins are the primary carriers of cholesterol in the blood. Apolipoprotein B-100 allows these particles to attach to specific receptors on the surface of cells, particularly in the liver. The receptors transport low-density lipoproteins into the cell, where they are broken down to release cholesterol. The cholesterol is then used by the cell, stored, or removed from the body.

How are changes in the APOB gene related to health conditions?

More than 90 mutations in the APOB gene have been found to cause familial hypobetalipoproteinemia (FHBL), a disorder that impairs the body's ability to absorb and transport fat. Most APOB gene mutations that cause FHBL lead to the production of apolipoprotein B that is abnormally short.

The severity of the condition largely depends on the length of the abnormal apolipoprotein B. Some mutations in the APOB gene lead to the production of a protein that is shorter than apolipoprotein B-100, but longer than apolipoproteinB-48. In these cases, normal apolipoprotein B-48 is still made in the intestine. The normal-length apolipoprotein B-48 can form chylomicrons normally, but the abnormally short apolipoprotein B-100 produced in the liver is less able to produce lipoproteins.

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Other mutations result in a protein that is shorter than both apolipoprotein B-48 and apolipoprotein B-100. In these cases, no normal-length apolipoprotein B protein is produced. The severely shortened protein is not able to form lipoproteins in the liver or the intestine. Generally, if both versions of the protein are shorter than apolipoprotein B-48, the signs and symptoms are more severe than if some normal length apolipoprotein B-48 is produced. All of these protein changes lead to a reduction of functional apolipoprotein B. As a result, the transportation of dietary fats and cholesterol is decreased or absent. A decrease in fat transport reduces the body's ability to absorb fats and fat-soluble vitamins from the diet, leading to the signs and symptoms of FHBL.

hypercholesterolemia - caused by mutations in the APOB gene

At least five mutations in the APOB gene are known to cause a form of inherited hypercholesterolemia called familial defective apolipoprotein B-100 (FDB). This condition is characterized by very high levels of cholesterol in the blood and an increased risk of developing heart disease. Each mutation that causes this condition changes a single protein building block (amino acid) in a critical region of apolipoprotein B-100. The altered protein prevents low-density lipoproteins from effectively binding to their receptors on the surface of cells. As a result, fewer low-density lipoproteins are removed from the blood, and cholesterol levels are much higher than normal. As the excess cholesterol circulates through the bloodstream, it is deposited abnormally in tissues such as the skin, tendons, and arteries that supply blood to the heart (coronary arteries). A buildup of cholesterol in the walls of coronary arteries

greatly increases a person's risk of having a heart attack.

Where is the APOB gene located?

Cytogenetic Location: 2p24-p23

Molecular Location on chromosome 2

What other names do people use for the APOB gene or gene products?

apoB-48

apoB-100

APOB_HUMAN

apolipoprotein B (including Ag(x) antigen)

http://ghr.nlm.nih.gov/gene/APOB

Apo B

is a protein that is involved in the metabolism of lipids and is the main protein constituent of lipoproteins such as very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL, the "bad cholesterol"). Concentrations of apo B tend to mirror those of LDL-C.

A health practitioner may order both an apo A-I (associated with high-density lipoprotein (HDL), the "good" cholesterol) and an apo B to determine an apoB/apo A-I ratio. This ratio is sometimes used as an alternative to a total cholesterol/HDL ratio to evaluate risk for developing CVD.

Apo B levels may be ordered to monitor the effectiveness of lipid treatment as an alternative to non-HDL-C (non-HDL-C is the total cholesterol concentration minus the amount of HDL).

In rare cases, an apo B test may be ordered to help diagnose a genetic problem that causes over- or under-production of apo B.

When is it ordered?Apo B may be measured, along with an apo A-I or other lipid tests, when a health practitioner is trying to evaluate someone's risk of developing CVD and when a person has a personal or family history of heart disease and/or abnormal lipid levels, especially when the person has significantly elevated triglyceride levels.

Sometimes apo B is ordered to monitor a person who is undergoing treatment for high cholesterol.

What does the test result mean?Elevated levels of apo B correspond to elevated levels of LDL-C and to non-HDL-C and are associated with an increased risk of cardiovascular disease (CVD). Elevations may be due to a high-fat diet and/or decreased clearing of LDL from the blood.

Some genetic disorders are the direct (primary) cause of abnormal levels of apo B. For example, familial combined hyperlipidemia is an inherited disorder causing high blood levels of cholesterol and triglycerides. Abetalipoproteinemia, also called Apolipoprotein B deficiency or Bassen-Kornzweig syndrome, is a very rare genetic condition that can cause abnormally low levels of apo B. For more on some of these disorders, see the Related Pages tab.

Abnormal levels of apo B can also be caused by underlying conditions or other factors (secondary causes). Increased levels of apo B are seen, for example, in:

Diabetes

Use of drugs such as: androgens, beta blockers, diuretics, progestins (synthetic progesterones)

Hypothyroidism

Nephrotic syndrome (a kidney disease)

Pregnancy (levels increase temporarily and decrease again after delivery)

Apo B levelsmay be decreased with any condition that affects lipoprotein

production or affects its synthesis and packaging in the liver. Lower levels are seen with secondary causes such as:

Use of drugs such as: estrogen (in post-menopausal women), lovastatin, simvastatin, niacin, and thyroxineHyperthyroidismMalnutritionReye syndromeWeight reductionSevere illnessSurgeryCirrohsisAn increased ratio of apo B to apo A-I may indicate a higher risk of developing CVD.

http://labtestsonline.org/understanding/analytes/apob/tab/test/

Effects of apoB truncation on lipid affinity

Several laboratories have reported a number of naturally occurring apoB gene mutations that produce truncated forms of apoB that range in length from 9% (apoB-9) to 89% (apoB-89) of full-length apoB-100

Because many domains throughout the entire length of apoB appear to be involved in lipid binding, truncated apoB is expected to form denser lipid-poor particles. For example, Parhofer et al.

demonstrated that apoB-89, apoB-75, and apoB-54.8 were secreted into the VLDL fraction, whereas apoB-31 was secreted into HDL. In general, the shorter the mutant apoB protein, the denser and more lipid poor the particle

In fact, studies on the expression of truncated forms of apoB in cultured cells have indicated that the size of the secreted particles and the amount of lipid per particle are proportional to the length of the truncated apoB

Some elevations of apo B-100 (and LDL-C) are due to mutations in the APOB gene that cause it to produce apo B-100 that is not recognized as easily by LDL receptors. Others are in the LDL receptor system of the liver cell that recognizes apo B-100. These genetic defects impede the clearing of LDL from the blood and result in accumulations of LDL in the circulation, increasing the risk of heart disease.

Chylomicrons, the lipoprotein particles that carry dietary lipids to the liver, contain a lipoprotein called apolipoprotein B-48. It is about half the size of apo B-100 and is structurally related to apo B-100. It is not considered a risk factor for atherosclerosis and is not measured as part of the apo-B test. The apo B test is specific for apo B-100.

http://labtestsonline.org/understanding/analytes/apob/tab/test/

APO E is an O-linked glycoprotein in three isoforms

and is synthesised by many tissues, including liver, brain, adipose tissue, and artery wall, but most is present in plasma lipoproteins derived primarily from the liver. It is involved in many aspects of lipid and lipoprotein homeostasis, both for the triacylglycerol-rich lipoproteins and HDL, but it is also important for lipid metabolism in brain and other tissues. In addition, it is believed to have some non-lipid related functions, for example on immune response and inflammation.

The function of APO E Apolipoprotein E has many functions in the body. When it is synthesized by the liver

as part of VLDL it functions in the transport of triglycerides to the liver tissue. It is also incorporated into HDL (as HDL-E) and functions in cholesterol distribution among cells. It is also incorporated into intestinally synthesized cholymicrons and transports dietary triglycerides and cholesterol. It is involved in lipid metabolism by mediating the receptor binding of apo-E lipoproteins to the LDL receptor. Receptor binding begins the cellular uptake of lipoproteins to be used in intracellular cholesterol metabolism

Apolipoprotein E is synthesized in several areas of the body. Approximately three-fourths of the plasma apo-E is synthesized in the liver. Liver apo-E is produced primarily by hepatic parenchymal cells, and it becomes a component of VLDL. The brain also produces a large amount of apo-E. Approximately one-third of the liver levels of apo-E are made by astrocytes, the star-shaped branching neuroglial cells that are found in the brain. Apo-E is also synthesized in the spleen, lungs, adrenals, ovaries, kidneys, muscle cells, and in macrophages (Mahley). The apo-E synthesized from macrophages is involved in reverse cholesterol transport, local redistribution of cholesterol, and protection against the development of artherosclerotic lesions

http://wwwchem.csustan.edu/chem4400/SJBR/Dawn971.htm

Isoforms of APO E There are three different isoforms of apolipoprotein E: apo-E 2, apo-E 3, And apo-E 4.

Apo-E 3 is the parent form and all others are compared to it. Apo-E 2 is different from apo-E 3 because a cysteine is substituted for arginine at residue 158. Apo-E 2 is associated with Type III Hyperproteinemia (where there is an excess of protein in the blood plasma) and it does not bind to the lipid receptor. In fact, apo-E 2 shows less than 2% of the normal receptor binding activity. Apo-E 4 has an arginine substituted for cysteine at residue 112. This residue is outside of the strongest lipid binding area and the substitution doesn't.affect the lipid binding ability of the apolipoprotein. Functionally, apo-E 4 still has 100% of normal receptor binding activity .

Apoliooprotein E uses different metabolic pathways in the body. one of these pathways is endocrine-like, and involves the redistribution of lipids among cells of different organs. It takes lipids from the areas where the lipid is synthesized and distributes them to other areas where the lipids are used or stored. Another pathway in paracrine-like, where the lipids are transported among cells in the same organ or tissue. Apo- E is also involved in various pathways that are unrelated to lipid transport, such as the stimulation of lymphocytes.

http://wwwchem.csustan.edu/chem4400/SJBR/Dawn971.htm

Apo D

is atypical in that it is very different in structure from other apolipoproteins, and it is expressed widely in mammalian tissues (most others are produced mainly in liver and intestine). In plasma, it is present mainly in HDL and to a lesser extent in LDL, where it may function as a multi-ligand binding protein capable of transporting small hydrophobic molecules such as arachidonic acid, steroid hormones, and cholesterol for metabolism or signalling.

APOD occurs in the macromolecular complex with lecithin-cholesterol acyltransferase. It is probably involved in the transport and binding of bilin. Appears to be able to transport a variety of ligands in a number of different contexts.http://www.uniprot.org/uniprot/P05090

The apolipoprotein (apo) B/apoA-I ratio

represents the balance between apoB-rich atherogenic particles and apoA-I-rich antiatherogenic particles, and this ratio is considered to be a marker of cardiovascular risk.

Although many studies have demonstrated the importance of the apoB/apoA-I ratio in predicting the presence or absence of cardiovascular disease, less is known about apoB/apoA-I ratio as a marker of plasma atherogenicity.

The main cause of errors in the estimation of the lipoprotein-related risk of cardiovascular disease when using the conventional lipid indexes is due to the wide variance of cholesterol within the low-density lipoprotein and high-density lipoprotein molecules; this variance is due to the active exchange of lipid components between lipoproteins.

the lipoprotein cholesterol concentration does not always correspond to lipoprotein concentration

ApoB is an essential structural component of very low-density lipoproteins, intermediate-density lipoproteins, and low-density lipoproteins. Because each particle of these lipoproteins contains one molecule of apoB, the total atherogenic particles number can be accurately estimated by measuring the plasma level of this apoprotein. In contrast, apoA-I, the major structural constituent of antiatherogenic high-density lipoproteins, exchanges between lipoproteins and the number of apoprotein molecules varies between lipoprotein particles. levels of apoA-I in plasma are strongly correlated with HDL levels. apoB and apoA-I are assumed to be superior markers for lipoprotein abnormalities

referenceshttp://my.americanheart.org/professional/ScienceNews/Lipids-Lipoproteins-and-Apolipoproteins-as-Risk-Markers-of-Myocardial-Infarcti_UCM_466004_Article.jsp

http://www.ncbi.nlm.nih.gov/pubmed/25848795

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http://www.atsjournals.org/doi/abs/10.1164/rccm.201411-1990OC#.VVhn67mqqko

References:http://www.ncbi.nlm.nih.gov/pubmed/6099394

http://www.ncbi.nlm.nih.gov/pubmed/15891389

http://www.ncbi.nlm.nih.gov/pubmed/11518754

http://www.els.net/WileyCDA/ElsArticle/refId-a0005909.html

http://www.nextprot.org/db/entry/NX_P04114

http://www.ncbi.nlm.nih.gov/gene/347

http://www.biovision.com/apo-d-human-recombinant-3157.html

http://www.ncbi.nlm.nih.gov/gene?cmd=Retrieve&dopt=full_report&list_uids=347

http://www.uniprot.org/uniprot/P04114