Apolipoproteins structure and function

Name:eman abdelraouf ahmed

The content

Definition

Structure

Function

references

introduction

Plasma 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 a protein that in humans is encoded by the APOBgene.

FunctionApolipoprotein B is the primary apolipoprotein of chylomicrons, VLDL, IDL, andLDL particles (LDL - known commonly by the misnomer "bad cholesterol" when in reference to both heart disease and vascular disease in general), which is responsible for carrying fat molecules (lipids), including cholesterol, around the body (within the water outside cells) to all cells within all tissues.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 a ligand for 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 deliver fats carried within into the cells).

Genetic disorders

High levels of ApoB are related to heart disease. Hypobetalipoproteinemia is a genetic disorder that can be caused by a mutation in the ApoBgene, APOB. Abetalipoproteinaemia is usually caused by a mutation in the MTP gene, MTP.Mutations in gene APOB100 can also cause familial 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 of apolipoprotein found in the chylomicronand Intermediate-density lipoprotein (IDLs) that is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.

ApoE is mainly produced by astrocytes, and transports cholesterol toneurons via ApoEreceptors, which are members of the low density lipoprotein receptor gene family.

FunctionAPOE is 299 amino acids long and transports lipoproteins, fat-soluble vitamins, and cholesterol into the lymph system and then into the blood.

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It is synthesized principally in the liver, but has also been found in other tissues such as the brain,kidneys, and spleen. In the nervous system, non-neuronal cell types, most notablyastroglia and microglia, are the primary producers of APOE, while neurons preferentially express the receptors for APOE. There are seven currently identified mammalian receptors for APOE

which belong to the evolutionarily conserved low density lipoprotein receptor gene family

APOE was initially recognized for its importance in lipoprotein metabolism andcardiovascular disease. Defects in APOE result in familial dysbetalipoproteinemiaaka type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterolandtriglycerides are the consequence of impaired clearance of chylomicron, VLDLand LDL remnants

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

In the field of immune regulation, a growing number of studies point to APOE's interaction with many immunological processes, including suppressing T cellproliferation, macrophage functioning regulation, lipid antigen presentation facilitation (by CD1) to natural killer T cell as well as modulation of inflammationand oxidation. 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 A1 is a protein that in humans is encoded by the APOA1gene.

It has a specific role in lipid metabolism. Recent report suggest thatAPOA1 mRNA is regulated by endogenously expressed antisense RNA.

Apolipoprotein A1 is the major protein component of high density lipoprotein (HDL) in plasma. Chylomicrons secreted from the intestinal enterocyte also contain apo A1, but it is quickly transferred to HDL in the bloodstream.

The protein promotes fat efflux, including cholesterol, from tissues to the liver for excretion. It is a cofactor for lecithin cholesterolacyltransferase (LCAT) which is responsible for the formation of most plasma cholesteryl 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 as ELISA or nephelometry.

Clinical significanceAs a major component of the high-density lipoprotein complex (protective "fat removal" particles), apo A1 helps to clear fats, including cholesterol, from white blood cells within artery walls, making the WBCs less likely to become fat overloaded, transform into foam cells, die and contribute to progressive atheroma. 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-II

is a protein that in humans is encoded by the APOA2 gene.

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-IV

The primary translation product of the APOA4 gene is a 396-residue preprotein, which undergoes proteolytic processing to yield apoA-IV, a 376-residue mature O-linked glycoprotein. In most mammals, including humans, apo A-IV synthesis is confined to the intestine; however in mice and rats hepatic synthesis also occurs.

Apo A-IV is secreted into circulation on the surface of newly synthesizedchylomicron particles. 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:activate lecithin-cholesterol

acyltransferase and cholesterylester transfer protein in vitro;play a role in the regulation of appetite and satiety in rodent

models;display anti-oxidant and anti-atherogenic properties in vitro

and in rodent models;modulate the efficiency of enterocyte and hepatic

transcellular lipid transport in vitro.

apoC-I

is a protein component of lipoproteins that in humans is encoded by the APOC1 gene.

apoC-I-structureThe protein encoded by this gene is a member of the apolipoprotein C family. This gene is expressed primarily in the liver, and it is activated when monocytesdifferentiate into macrophages. A pseudogene of 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 57 amino acids normally 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 of CETP, probably by altering the electric charge of HDL molecules.

During fasting (like other apolipoprotein C), it is found primarily within HDL, 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 charged proteins in the human body.

Apolipoprotein C2The protein encoded by this gene is secreted in plasma where it is a component ofvery low density lipoproteins and chylomicrons. This protein activates the enzymelipoprotein lipase in capillaries,[1] which hydrolyzes triglycerides and thus provides free fatty acids for cells. Mutations in this gene cause hyperlipoproteinemia type IB, characterized by xanthomas, pancreatitis, and hepatosplenomegaly, but no increased risk for atherosclerosis. Lab tests will show elevated blood levels of triglycerides, cholesterol, and chylomicrons.

apo-CIIIalso known as apo-CIII is a protein that in humans is encoded by the APOC3 gene. Apo-CIII is a component of very low density lipoprotein (VLDL).

Structure

ApoCIII is a relatively small protein containing 79 amino acids that can be glycosylated at threonine-74.The most abundant glycoforms are characterized by an O-linked disaccharide galactose linked to N-acetylgalactosamine (Gal-GalNAc), further modified with up to 2 sialicacid residues. Less abundant glycoforms are characterized by more complex and fucosylated glycan moieties.

FunctionAPOC3 inhibits lipoprotein lipase and hepatic lipase; it is thought to inhibit hepatic uptake[.of triglyceride-rich particles. The APOA1, APOC3 and APOA4 genes are closely linked in both rat and human genomes. 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 susceptibility haplotypes (specifically, P2-S2-X1 and P1-S2-X1) have been discovered in ApoAI-CIII-AIV gene cluster onchromosome 11q23; these confer approximately threefold higher risk of coronary heart disease in normal as 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

http://www.scientificpsychic.com/health/lipoproteins-LDL-HDL.html