Structure lipoproteins

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Apolipoproteins structure and function

Apolipoproteins structure and functionName:eman abdelraouf ahmed

The contentDefinition StructureFunctionreferences

introductionPlasma lipoprotein metabolism is regulated and controlled by the specific apolipoprotein (apo-) constituents of the various lipoprotein classes. The major apolipoproteins include apoE, apoB, apoA-I, apoA-II, apoA-IV, apoC-I, apoC-II, and apoC-III.

Apolipoprotein B(ApoB)is aproteinthat in humans is encoded by theAPOBgene.


Apolipoprotein B is the primaryapolipoproteinofchylomicrons,VLDL,IDL, andLDLparticles (LDL - known commonly by themisnomer"badcholesterol" when in reference to bothheart diseaseandvascular diseasein general), which is responsible for carryingfatmolecules (lipids), includingcholesterol, around the body (within the water outside cells) to allcellswithin alltissues. it is the primary organizing protein (of the entire complex shell enclosing/carrying fat molecules within) component of the particles and is absolutely required for the formation of these particles. What is also clear is that the ApoB on the LDL particle acts as aligandfor LDL receptors in various cells throughout the body (i.e., less formally, ApoB indicates fat carrying particles are ready to enter any cells with ApoB receptors and deliverfatscarried within into the cells).Genetic disorders

High levels of ApoB are related to heart disease.Hypobetalipoproteinemiais agenetic disorderthat can be caused by a mutation in the ApoB gene,APOB.Abetalipoproteinaemiais usually caused by a mutation in the MTP gene,MTP.Mutations in geneAPOB100can also causefamilial hypercholesterolemia, a hereditary (autosomal dominant) form of metabolic disorderHypercholesterolemia.Specific apolipoproteins function in the regulation of lipoprotein metabolism through their involvement in the transport and redistribution of lipids among various cells and tissues, through their role as cofactors for enzymes of lipid metabolism, or through their maintenance of the structure of the lipoprotein particles. The primary structures of most of the apolipoproteins are now known, and various functional domains of these proteins are being mapped using selective chemical modification, synthetic peptides, and monoclonal antibodies.

apoEApolipoprotein E(ApoE) is a class ofapolipoproteinfound in thechylomicronandIntermediate-density lipoprotein (IDLs)that is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.ApoE is mainly produced byastrocytes, and transportscholesteroltoneuronsvia ApoE receptors, which are members of thelow density lipoprotein receptor gene family.Function

APOE is 299amino acidslong and transportslipoproteins, fat-solublevitamins, andcholesterolinto thelymph systemand then into the blood..

It is synthesized principally in theliver, but has also been found in other tissues such as thebrain,kidneys, andspleen. In the nervous system, non-neuronal cell types, most notablyastrogliaandmicroglia, are the primary producers of APOE, while neurons preferentially express the receptors for APOE. There are seven currently identified mammalianreceptorsfor APOE which belong to the evolutionarily conservedlow density lipoprotein receptor gene familyAPOE was initially recognized for its importance in lipoprotein metabolism andcardiovascular disease. Defects in APOE result infamilial dysbetalipoproteinemiaaka type IIIhyperlipoproteinemia(HLP III), in which increased plasmacholesteroland triglycerides are the consequence of impaired clearance ofchylomicron,VLDLandLDLremnants

More recently, it has been studied for its role in several biological processes not directly related to lipoprotein transport, includingAlzheimer's disease(AD),immunoregulation, andcognition.

In the field of immune regulation, a growing number of studies point to APOE's interaction with many immunological processes, including suppressingT cellproliferation,macrophagefunctioning regulation, lipid antigen presentation facilitation (byCD1)tonatural killer T cellas well as modulation ofinflammationandoxidation.ApoE is produced by macrophages and apoE secretion has been shown to be restricted to classical monocytes in PBMC, and the secretion of apoE by monocytes is down regulated by inflammatory cytokines and upregulated by TGF-beta.apoA-IApolipoprotein A1is aproteinthat in humans is encoded by theAPOA1gene.It has a specific role inlipid metabolism. Recent report suggest thatAPOA1mRNA is regulated by endogenously expressed antisense RNA.Apolipoprotein A1 is the major protein component ofhigh density lipoprotein(HDL) inplasma.Chylomicronssecreted from the intestinal enterocyte also contain apo A1, but it is quickly transferred to HDL in the bloodstream.The protein promotes fat efflux, includingcholesterol, from tissues to the liver for excretion. It is a cofactor forlecithin cholesterolacyltransferase(LCAT) which is responsible for the formation of most plasmacholesteryl esters. Apo A1 was also isolated as aprostacyclin(PGI2) stabilizing factor, and thus may have an anticlotting effect.ApoA1 is often used as a biomarker for prediction of cardiovascular diseases and the ratio apoB- 100/apoA1 has been reported as a stronger predictor for the risk of myocardial infarction than any other lipid measurement.ApoA1 is routinely measured using immunoassays such asELISAornephelometry.Clinical significance

As a major component of thehigh-density lipoproteincomplex (protective "fat removal" particles), apo A1 helps to clear fats, includingcholesterol, from white blood cells within artery walls, making the WBCs less likely to become fat overloaded, transform into foam cells, die and contribute to progressiveatheroma. Five of nine men found to carry a mutation (E164X) who were at least 35 years of age had developed premature coronary artery disease.One of four mutants of apo A1 is present in roughly 0.3% of the Japanese population, but is found in 6% of those with low HDL cholesterol levels.Apolipoprotein A-IIis aproteinthat in humans is encoded by theAPOA2gene.This gene encodes apolipoprotein (apo-) A-II, which 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. Defects in this gene may result in apolipoprotein A-II deficiency or hypercholesterolemia.apoA-IVThe primary translation product of the APOA4 gene is a 396-residue preprotein, which undergoes proteolytic processing to yield apo A-IV, a 376-residue mature O-linked glycoprotein. In most mammals, including humans, apo A-IV synthesis is confined to theintestine; however in mice and rats hepatic synthesis also occurs.Apo A-IV is secreted into circulation on the surface of newly synthesizedchylomicronparticles. Intestinal fat absorption dramatically increases the synthesis and secretion of apo A-IV. Although its primary function in human lipid metabolism has not been established, apo A-IV has been found to:activatelecithin-cholesterol acyltransferaseandcholesterylester transfer proteinin vitro;play a role in the regulation ofappetiteandsatietyin rodent models;displayanti-oxidantand anti-atherogenicproperties in vitro and in rodent models;modulate the efficiency of enterocyte and hepatic transcellularlipidtransport in vitro.

apoC-Iis a protein component oflipoproteinsthat in humans is encoded by theAPOC1gene.

apoC-I-structureThe protein encoded by this gene is a member of theapolipoprotein Cfamily. This gene is expressed primarily in the liver, and it is activated whenmonocytesdifferentiate intomacrophages. Apseudogeneof this gene is located 4 kb downstream in the same orientation, on the same chromosome. This gene is mapped to chromosome 19, where it resides within an apolipoprotein gene cluster. Alternatively spliced transcript variants have been found for this gene, but the biological validity of some variants has not been determined.Apolipoprotein C1 has a length of 57amino acidsnormally found in plasma and responsible for the activation of esterified lecithin cholesterol with an important role in the exchange of esterified cholesterol between lipoproteins and in removal of cholesterol from tissues. Its main function is inhibition ofCETP, probably by altering theelectric chargeofHDLmolecules.During fasting (like otherapolipoproteinC), it is found primarily withinHDL, while after a meal it is found on the surface of other lipoproteins. When proteins rich in triglycerides like chylomicrons and VLDL are broken down, this apoprotein is transferred again to HDL. It is one of the most positively chargedproteinsin the human body.Apolipoprotein C2The protein encoded by this gene is secreted in plasma where it is a component ofvery low density lipoproteinsandchylomicrons. This protein activates the enzymelipoprotein lipasein capillaries,[1]which hydrolyzes triglycerides and thus provides freefatty acidsfor cells. Mutations in this gene causehyperlipoproteinemia type IB, characterized byxanthomas,pancreatitis, and hepatosplenomegaly, but no increased risk foratherosclerosis. Lab tests will show elevated blood levels of triglycerides, cholesterol, and chylomicrons.apo-CIIIalso known asapo-CIIIis aproteinthat in humans is encoded by the APOC3gene. Apo-CIII is a component ofvery low density lipoprotein(VLDL).


ApoCIII is a relatively small protein containing 79 amino acids that can beglycosylatedatthreonine-74.The most abundant glycoforms are characterized by an O-linked disaccharide galactose linked toN-acetylgalactosamine(Gal- GalNAc), further modified with up to 2sialic acidresidues. Less abundant glycoforms are characterized by more complex andfucosylatedglycanmoieties.Function

APOC3 inhibitslipoprotein lipaseandhepatic lipase; it is thought to inhibit hepatic uptake[.oftriglyceride-rich particles. TheAPOA1, APOC3 andAPOA4genes are closely linked in both rat and humangenomes. The A-I and A-IV genes are transcribed from the same strand, while the A-1 and C-III genes are convergently transcribed. An increase in apoC-III levels induces the development ofhypertriglyceridemia. Recent evidences suggest an intracellular role for Apo-CIII in promoting the assembly and secretion of triglyceride-rich VLDL particles from hepatic cells under lipid-rich conditions.However, two naturally occurring point mutations in human apoC3 coding sequence, namely Ala23Thr and Lys58Glu have been shown to abolish the intracellular assembly and secretion of triglyceride-rich VLDL particles from hepatic cells.Clinical significance

Two novel susceptibilityhaplotypes(specifically, P2-S2-X1 and P1-S2-X1) have been discovered in ApoAI-CIII-AIVgene clusteronchromosome11q23; these confer approximately threefold higher risk ofcoronary heart diseasein normalas well as non-insulindiabetes mellitusApo-CIII delays the catabolism of triglyceride rich particles. Elevations of Apo-CIII found in genetic variation studies may predispose patients to non-alcoholic fatty liver disease.references