NON-PROTEIN NITROGEN CONTAINING AND NITROGEN NOT CONTAINING ORGANIC COMPONENTS OF BLOOD

Non–protein nitrogen containing and nitrogeot containing norganic components of blood. nBiochemical composition of blood iorm and pathology: protein plasma, nacute phase proteins, enzymes of blood plasma

 

The total content of protein in blood plasma.

The total contents of proteins in blood plasma is n65-85 g/l. The increase of protein level in blood is called hyperproteinemia nand decrease – hypoproteinemia.

The fractions of blood plasma proteins.

There are different proteins in blood plasma distinguished by the physical, nchemical and functional properties: transport proteins, enzymes, proenzymes, ninhibitors of enzymes, hormones, antibodies, antitoxins, factors of coagulatioand anticoagulators and others.

The quantity of separate nprotein fractions depend on the method of separation. In paper electrophoresis nblood plasma proteins can be separated on 5 fractions: albumins (40-50 g/l), a₁-globulins n(3-6 g/l), a₂-globulins n(4-9 g/l), b-globulins n(6-11 g/l) and g-globulins n(7-15 g/l).

Albumins – nmultidispersed fraction of blood plasma which are characterized by the high electrophoretic mobility and mild dissolubility in water and saline solutions. nMolecular weight of albumins is about 60000. Due to high hydrophilic properties albumins bind a significant namount of water, and the volume of their molecule under hydratation is doubled. Hydrative layer nformed around nthe serum albumins provides to 70-80 % of oncotic pressure of blood plasma nproteins, that can be applied in clinical practice at albumins transfusion to npatients with tissue edemas. The decreasing of albumins concentration in blood nplasma, for example under disturbance of their synthesis in hepatocytes at liver failure, can cause the water transition from a vessels ninto the tissues and development of oncotic edemas.

Albumins execute also nimportant physiological function as transporters of a lot of metabolites and ndiverse low molecular weight structures. The molecules of albumins have  several sites with centers of linkage for molecules nof organic ligands, which are affixed by the electrostatic and hydrophobic bonds. Serum albumins can affix and convey fatty acids, ncholesterol, cholic pigments (bilirubin and that similar), vitamins, hormones, nsome amino acids,  toxins and medicines.

Albumins also execute the nbuffer function. Due to the availability in their structure amino and ncarboxylic groups albumins can react both as acids and as alkaline.

Albumins can bound ndifferent toxins in blood plasma (bilirubin, foreign substances et c.). This is nthe desintoxicative  function of nalbumins.

Albumins also play role of namino acids depot in the organism. They can supply amino acids for the building nof another proteins, for example enzymes.

Globulins – nheterogeneous fraction of blood proteins which execute transport (a₁-globulins – ntransport of lipids, thyroxin, corticosteroid hormones; a₂-globulins – ntransport of lipids, copper ions; b-globulins – ntransport of lipids, iron) and protective (participation of b-globulins in immune nreactions as antitoxins; g-globulins nas immunoglobulins) functions. They also support the blood oncotic pressure and nacid-alkaline balance, provide amino acids for the organism requirements. The nmolecular weight of globulins is approximately 150000-300000.

The globulin level in blood nplasma is 20-40 g/l. A ratio between concentrations of albumins and globulins n(so called “protein coefficient”) in blood plasma is often determined iclinical practice. In healthy people this coefficient is 1,5-2,0.

Fibrinogen – important nprotein of blood plasma, precursor of fibrin, the structural element of blood nclots. Fibrinogen participates in blood clotting and thus prevents the loss of nblood from the vascular system of vertebrates. The approximate molecular weight nof fibrinogen is 340000. It is the complex protein, it contains the ncarbohydrate as prosthetic group. The content of firinogen in blood is 3-4 g/l.

Subfractions of a₁, a₂, b and g globulins, their structure and functions.

Immunoglobulins  (Ig A, Ig G, Ig E, Ig M) – proteins of g-globulin fraction of blood nplasma executing the functions of antibodies which are the main effectors of nhumoral immunity. They appear in the blood serum and certain cells of a nvertebrate in response to the introduction of a protein or some other macromolecule nforeign to that species.

Immunoglobulin molecules nhave bindind sites that are specific for and complementary to the structural nfeatures of the antigen that induced their formation. Antibodies are highly nspecific for the foreign proteins that evoke their formation.

Molecules of nimmunoglobulins  are glycoproteins. The nprotein part of immunoglobulins  contaifour polipeptide chains: two heavy H-chains and two light L-chains.

C-reactive protein (g-fraction). This proteireceived the title owing to its capacity to react with C-polysaccharide of a npneumococcus forming precipitates. According to its chemical nature C-reactive nprotein is glycoprotein.

In blood plasma of healthy people nthe C-reactive protein is absent but it occurs at npathological states accompanied by an inflammation and necrosis of tissues. The navailability of C-reactive protein is characteristic for the acute period of ndiseases – “protein of an acute phase”. The determination of C-reactive proteihas diagnostic value in an acute phase of rheumatic disease, at a myocardial ninfarction, pneumococcal, streptococcal, staphylococcal infections.

Crioglobulin – the nprotein of the g-globulifraction. Like to the C-reactive protein crioglobulin absent in blood plasma of nthe healthy people and occurs at leukoses, rheumatic disease, liver cirrhosis, nnephroses. The characteristic physico-chemical feature of crioglobulin is its ndissolubility at standard body temperature (37 ^oC) and capacity to nform the sediment at cooling of a blood plasma up to 4 ^oC.

a₂-macroglobulin – proteiof a₂-globulifraction, universal serum proteinase inhibitor. Its contents (2,5 g/l) in blood nplasma is highest comparing to another proteinase inhibitors.

The biological role of a₂-macroglobuliconsists in regulation of the ntissue proteolysis systems which are very important nin such physiological and pathological processes as blood clotting, fibrinolysis, processes of immunodefence, functionality of a complement nsystem, inflammation, regulation of vascular ntone (kinine and renin-angiothensine system).

a₁-antitrypsin (a₁-globulin) – nglycoprotein with a molecular weight 55 nkDa. Its concentration in blood plasma is 2-3 г/л. The main biological property of this inhibitor is its capacity to form ncomplexes with proteinases oppressing proteolitic activity of such enzymes as trypsin, chemotrypsin, nplasmin, trombin. The content of a₁-antitrypsiis markedly increased in inflammatory processes. The inhibitory activity of a₁-antitrypsiis very important in pancreas necrosis and acute pancreatitis because in these nconditions the proteinase level in blood and tissues is sharply increased. The ncongenital deficiency of a₁-antitrypsiresults in the lung emphysema.

Fibronectin – nglycoprotein of blood plasma that is synthesized and secreted nin intercellular space by different cells. Fibronectin present on a surface of cells, on the basal membranes, in connective ntissue and in blood. Fibronectin has nproperties of a «sticking» protein and contacts nwith the carbohydrate groups of gangliosides non a surface of plasma membranes executing the integrative function in intercellular interplay. Fibronectin also plays important role in the formation of the pericellular matrix.

Haptoglobin – proteiof a₂-globulifraction of  blood plasma. Haptoglobin has capacity to bind a free haemoglobin forming a complex nthat refer to b-globulins nelectrophoretic fraction. Normal concentration in blood plasma – 0,10-0,35 g/l.

Haptoglobin-hemoglobin complexes nare absorbed by the cells of reticulo-endothelial nsystem, in particular in a liver, and oxidized to cholic pigments. Such haptoglobin function promotes the preservation of iron ions in aorganism under conditions of a physiological and pathological erythrocytolysis. n

Transferrin – glycoprotein belonging to the b-globulin fraction. It nbinds in a blood plasma iron ions (Fe³⁺). The protein has on the nsurface two centers of linkage of iron. Transferrin is a transport form of iron delivering its to places nof  accumulation and usage.

Ceruloplasmin – glycoprotein of the a₂-globulifraction. It can bind the copper ions in blood plasma. Up to 3 % of all copper ncontents in an organism and more than 90 % copper contents in plasma is included iceruloplasmin. Ceruloplasmin has properties of nferroxidase oxidizing the iron  ions. The decrease of ceruloplasmin in organism (Wilson disease) results in exit of copper ions from vessels and its naccumulation in the connective tissue that shows by pathological changes in a nliver, main brain, cornea.

The place of synthesis of each fraction and nsubfruction of blood plasma proteins.

Albumins, a₁-globulins, nfibrinogen are fully synthesized in hepatocytes. Immunoglobulins are produced nby plasmocytes (immune cells). In liver cryoglobulins and some other  g-globulins are produced too.  a₂-globulins nand b-globulins are partly synthesized in liver and partly nin reticuloendothelial cells.

Causes and consequences of protein content changes iblood plasma.

Hypoproteinemia  – decrease of the total contents of proteins nin blood plasma. This state occurs in old people as well as in pathological nstates accompanying with the oppressing of protein synthesis (liver diseases) nand activation of decomposition of tissue proteins (starvation, hard infectious ndiseases, state after hard trauma and operations, cancer). Hypoproteinemia n(hypoalbuminemia) also occurs in kidney diseases, when the increased excretioof proteins via the urine takes place.

Hyperproteinemia  – increase of the total contents of proteins in blood nplasma. There are two types of  nhyperproteinemia – absolute nand relative.

Absolute hyperproteinemia – accumulation of the nproteins in blood. It occurs in infection and inflammatory diseases n(hyperproduction of immunoglobulins),  nrheumatic diseases (hyperproduction of C-reactive protein), some nmalignant tumors (myeloma) and others.

Relative hyperproteinemia – the increase of the proteiconcentration but not the absolute amount of proteins. It occurs when organism nloses water (diarrhea, vomiting, fever, intensive physical activity etc.).

The principle of the measurement of protein fractions nby electrophoresis method.    

Electrophoresis is the separation of proteins on the nbasis of their electric charge. It depends ultimately on their base-acid properties, nwhich are largely determined by the number and types of ionizable R groups itheir polipeptide chains. Since proteins differ in amino acid composition and nsequence, each protein has distinctive acid-base properties. There are a number nof different forms of electroforesis useful for analyzing and separating nmixtures of proteins.

Residual nitrogen – nonproteiitrogen, that is nitrogen of organic and ninorganic compounds that remain in blood after protein sedimentation.

Organic and ninorganic compounds of residual nitrogen are as follows: urea (50 % of the nresidual nitrogen), amino acids (25 %), creatine and creatinine (7,5 %), salts nof ammonia and indicane (0,5 %), other compounds (about 13 %).

Urea is nformed in liver during the degradation of amino acids, pyrimidine nucleotides nand other nitrogen containing compounds. Amino acids are formed as result of nprotein decomposition or owing to the conversion of fatty acids or ncarbohydrates to amino acids. The pool of amino acids in blood is also nsupported by the process of their absorption in intestine. Creatine is produced nin kidneys and liver from amino acids glycine and arginine, creatinine is nformed in muscles as result of creatine phosphate splitting. In result of nammonia neutralization the ammonia salts can be formed. Indicane is the product nof indol neutralization in the liver.

The content of residual nitrogen in blood is 0,2 – 0,4 g/l.

 The pathways of convertion of amino acid nonnitrogen residues.

The removal of the amino group nof an amino acid by transamination or oxidative deamination produces aα-keto acid that contains the carbon skeleton from the amino acid (nonnitrogen residues). These α-keto nacids can be used for the biosynthesis of non-essential amino acids or nundergoes a different degradation process. For alanine and serine, the ndegradation requires a single step. For most carbon arrangements, however, nmultistep reaction sequences are required.  nThere are only seven degradation sequences for 20 amino acids. The sevedegradation products are pyruvate, acetyl CoA, acetoacetyl CoA, nα-ketoglutarate, succinyl CoA, fumarate, and oxaloacetate. The last four nproducts are intermediates in the citric acid cycle. Some amino acids have more nthan one pathway for degradation.

The major npoint of entry into the tricarboxylate cycle is via acetyl-CoA; 10 amino acids nenter by this route. Of these, six (alanine, glycine, serine, threonine, ntryptophan and cysteine) are degraded to acetyl-CoA via pyruvate, five (phenylalanine, tyrosine, leucine, lysine, nand tryptophan) are degraded via acetoacetyl-CoA, and three (isoleucine, nleucine and tryptophan) yield nacetyl-CoA directly.  Leucine and ntryptophan yield both acetoacetyl-CoA and acetyl-CoA as end products.

The carboskeletons of five amino acids (arginine, nhistidine, glutamate, glutamine and proline) enter the tricarboxylic acid ncycle via a-ketoglutarate.

The carboskeletons of methionine, isoleucine, and nvaline are ultimately degraded via propionyl-CoA and methyl-malonyl-CoA to nsuccinyl-CoA; these amino acids are thus glycogenic.

Fumarate nis formed in catabolism of phenylalanine, naspartate and tyrosine.

Oxaloacetate nis formed in catabolism of aspartate and nasparagine. Aspartate is converted to the oxaloacetate by transamination.

Amino acids that nare degraded to citric acid cycle intermediates can serve as glucose precursors nand are called glucogenic. A glucogenic amino acid is an amino acid nwhose carbon-containing degradation product(s) can be used to produce glucose nvia gluconeogenesis.

Amino nacids that are degraded to acetyl CoA or acetoacetyl CoA can contribute to the nformation of fatty acids or ketone bodies and are called ketogenic. A ketogenic namino acid is an amino acid whose ncarbon-containing degradation product(s) can be used to produce ketone bodies. n

Amino nacids that are degraded to pyruvate can be either glucogenic or ketogenic. nPyruvate can be metabolized to either oxaloacetate (glucogenic) or acetyl CoA n(ketogenic).

Only two namino acids are purely ketogenic: leucine and lysine. Nine amino acids nare both glucogenic and ketogenic: those degraded to pyruvate (alanine, nglycine, cysteine, serine, threonine, tryptophan), as well as tyrosine, nphenylalanine, and isoleucine (which have two degradation products). The remaining nnine amino acids are purely glucogenic (arginine, asparagine, aspartate, nglutamine, glutamate, valine,  histidine, nmethionine, proline)

The regulation of proteimetabolism. Protein metabolism nis regulated by different hormones. All hormones according to their action oprotein synthesis or splitting are divided on two groups: anabolic and ncatabolic. Anabolic hormones promote to the protein synthesis. Catabolic nhormones enhance the decomposition of proteins.

Somatotropic hormone (STH, growth nhormone):

–          nstimulates the npassing of amino acids into the cells;

–     activates nthe synthesis of proteins, DNA, RNA.

Thyroxine nand triiodthyronine:

–      iormal nconcentration stimulate the synthesis of proteins and nucleic acids;

–      nin excessive concentration activate the catabolic nprocesses.

Insulin:

–      nincreases the npermeability of cell membranes for amino acids;

–      nactivates nsynthesis of proteins and nucleic acids;

–      ninhibits the nconversion of amino acids into carbohydrates.

Glucagon:

–      nstimulates the conversioof amino acids into carbohydrates.

Epinephrine:

– nactivates the protein decomposition.

Glucocorticoids:

–      nstimulate nthe catabolic processes (protein decomposition) in connective, lymphoid and nmuscle tissues and activate the processes of protein synthesis in liver;

–      nstimulate nthe activity of aminotransferases;

–      nactivate nthe synthesis of urea.

Sex nhormones:

–      nstimulate nthe processes of protein, DNA, RNA synthesis;

–      ncause nthe positive nitrogenous balance.

The role of liver in proteimetabolism:

–     nsynthesis nof plasma proteins.  Most nof plasma proteins are synthesized in liver: all albumins, 75-90 % of nα-globulins, 50 % of β-globulins, all proteins of blood clotting nsystems (prothrombin, fibrinogen, proconvertin, proaccelerine). Only nγ-globulins are synthesized in the cells of reticuloendothelial system.

–     nsynthesis nof urea and uric acid;

–     nsynthesis nof choline and creatine;

–     ntransaminatioand deamination of amino acids.

Clinical significance of residual nnitrogen measurement in blood. The kinds of azotemia.

Azotemia  – increase nof the residual nitrogen content in blood. There are two kinds of azotemia: absolute and relative.

Absolute azotemia – naccumulation of the components of residual nitrogen in blood. Relative azotemia occurs in dehydratioof the organism (diarrhea, vomiting).

Absolute nazotemia can be divided on the productive nazotemia and retention azotemia. nRetention azotemia is caused by the poor excretion of the nitrogecontaining compounds via the kidneys; in this case the entry of nitrogecontaining compounds into the blood is normal.

Retention azotemia can be divided on the renal and extrarenal. Renal retention azotemia occurs in kidney ndiseases (glomerulonephritis, pyelonephritis, kidney tuberculosis et c.). Extrarenal retention azotemia is caused nby the violations of kidney hemodynamic and decrease of glomerulus filtratioprocesses (heart failure, local disorders of kidney hemodynamic).

Productive azotemia is conditioned by the enhanced entry of nitrogecontaining compounds into the blood. The function of kidneys in this case ndoesn’t suffer. Productive azotemia can be observed in cachexia, leukoses, malignant tumors, treatment by glucocorticoids.

Lipoproteins and nApoproteins

Lipids are a group of fatty substances that includes ntriglycerides (fat), phospholipids and sterols (e.g. cholesterol).  They nconstitute an important source of energy, serve as precursors for a number of nessential compounds, and are key components of cells and tissues.  nCholesterol, for example, is an indispensable constituent of cellular membranes (1), as nwell as the precursor for both steroid hormones and bile acids.  Oaverage, the body utilizes approximately 1000 milligrams of cholesterol per nday, 30% of which comes directly from foods of animal origin, and the rest is nsynthesized in the liver. Due to the insolubility of cholesterol and other nfatty compounds in the blood, their redistribution in the body requires nspecialized carriers capable of solubilzing, ferrying, and unloading them at nspecific target sites. Miscarriage of lipids while in circulation may lead to natherosclerosis; a clinical condition marked by fatty deposits in the inner nwalls of arteries, and the leading cause of death and disability in Westercountries.

Most lipids are transported in the blood as part of soluble complexes ncalled lipoproteins (LPs). Plasma LPs are spherical particles composed of a nhydrophobic lipid core surrounded by a hydrophilic layer, which renders the nparticles soluble. The lipid core contains primarily triglycerides (TG) and ncholesteryl esters (CE), as well as small amounts of other fatty compounds, nsuch as sphingolipids and fat-soluble vitamins (e.g. vitamins A, D, E, and K). nThe external layer is made of phospholipids, unesterified cholesterol, and nspecialized proteins, called apolipoproteins or apoproteins. These proteins nfacilitate lipid solubilization and help to maintain the structural integrity nof LPs. They also serve as ligands for LP receptors and regulate the activity nof LP metabolic enzymes. As depicted in (Figure 1), the amphipathic nmolecules that compose the outer layer of LPs are arranged so that their nhydrophobic parts face the central core, and their hydrophilic regions face the nsurrounding aqueous environment.

Cholesteryl esters, which do not contain a free hydroxyl group (-OH) are nmore hydrophobic than cholesterol, and better accommodated in the core of LPs. nThe conversion of cholesterol to CE is catalyzed by a LP-associated enzyme ncalled lecithin-cholesterol acyltransferase (LCAT). This enzyme, which promotes npackaging of cholesteryl molecules in LPs, is critical for normal cholesterol nmetabolism. Deficiency of LCAT activity leads to accumulation of unesterified cholesterol nin tissues, and is associated with a number of clinical conditions including ncorneal opacity, hemolytic anemia, and premature atherosclerosis.

During ordinary metabolism, plasma LPs lose, acquire, and exchange their nlipid and protein constituents. Normally, fat-rich LPs lose most of their fat nwithin a few hours of food ingestion, and become smaller and denser particles nwith higher relative cholesterol content. The depletion of fat from LPs is ncatalyzed by lipoprotein lipase (LPL). This lipolytic enzyme is located on the nsurface of endothelial capillaries, and degrades triglycerides to free fatty nacids (FFAs) and glycerol. The released FFAs may stay in circulation bound to nalbumin, or be taken-up by muscle and fat cells for usage and storage, nrespectively.

Lipids of dietary origin are processed by intestinal epithelial cells, nand then secreted into the bloodstream as part of large, fat-rich LPs called nchylomicrons (chylo = milky, micron= indicates particle size).  En route nto the liver, chylomicrons (CM) pass through endothelial capillaries, lose some nfat, and their remnants are taken-up by liver cells. In the liver, the lipids obtained nfrom CM remnants are re-processed and then secreted back into the bloodstream nas part of very low-density LPs (VLDL). Depletion of fat from VLDL transforms nthe particle into an intermediate density lipoprotein (IDL), which upon further ndegradation of its fat is converted into a relatively stable particle, called nlow density lipoprotein (LDL). Because of its high cholesterol content, LDL is nalso called LDL-cholesterol. Of the total blood cholesterol, 60-75% is found iLDL and the rest primarily in high-density lipoprotein (HDL) particles. The nmain characteristics of plasma LPs and their associated apoproteins are nsummarized in (Tables I and II), respectively.

 

 

All peripheral cells express the LDL-receptor (LDLR), and nrecycle it to the cell surface upoeed for cholesterol. Cholesterol is ndelivered to these cells through binding of LDL to LDLR, which triggers nendocytosis (internalization) of both species. When the need for cholesterol is nsatisfied, the recycling of LDLR is discontinued.  Normally, an LDL nparticle stays in circulation for no more than a few days before being consumed nby a cholesterol needing cell. However, under conditions of sustained ncholesterol excess, the particle stays in circulation for longer periods of ntime, and becomes more vulnerable to undesired modifications (e.g. oxidation). nAs high levels of oxidized LDL are commonly found in atherosclerotic plaques, nthey are thought to be the major inducer of atherosclerotic lesions. Hence, LDL nbecame known as bad cholesterol. However, today we know that not all LDL nparticles are bad, and that some LDL particles, especially very large ones n(with diameter >21.3nm), may even provide protection against natherosclerosis (2).  LDL and HDL particle sizes are largely ndetermined by a LP-associated protein, called CETP (cholesteryl ester transfer nprotein). This protein enhances exchange of non-polar lipids, primarily CE and nTG, and facilitates tight packaging of CE within the core of the particles. The nend result of prolonged and/or efficient CETP action is smaller LDL and HDL nparticles. [The LP-anchored CETP can be envisioned as having a hand that nrotates between the interior and exterior of the particle and  capable of nholding only one lipid molecule at a time. Grasping of one molecule releases nanother and vise versa.]

Genetic variation at the human CETP gene generates nproteins with varying degrees of activity.  For example, a single codovariation, from isoleucine to valine at position 405, generates a mutant protein, ndesignated I405V, which manifests significantly reduced CETP activity (3, n4). In a new observational study, Barzilai, N. et al. (2) found nthat people with homozygosity for the I405V allele have larger HDL and LDL nparticles, and that this genotype is associated with exceptional longevity and na markedly reduced risk of coronary artery disease (CAD). Of the 213 ncentenarians enrolled in the study, 80% had a high proportion of large LDL nparticles, compared to just 8% of the subjects in the control group (256 people nin their 60’s and 70’s) (2). Interestingly, HDL and LDL particle nsizes are significantly larger in women than in men, which may account, at nleast in part, for the longer life expectancies of women.

Unlike LDL, HDL is not recognized by LDLR, and cannot ndeliver cholesterol to tissue cells. Instead, it has the ability to remove nexcess peripheral cholesterol and return it to the liver for recycling and nexcretion. This process, called reverse cholesterol transport, is thought to nprotect against atherosclerosis. Observational studies over the last 2 decades nhave consistently shown strong correlation between elevated HDL levels and low nincidents of coronary heart disease (CHD). Hence HDL has been dubbed “good” ncholesterol.

HDL is synthesized in the liver and intestine as a nnascent, discoid-shaped particle that contains predominantly apoA-I, and some nphospholipids. Upon maturation, HDL assumes a spherical shape, and the ncomposition of its core lipids becomes very similar to that of LDL. However, nthe relative higher protein content in HDL renders the particle denser and more nresistant to undesired modifications. Unlike the case of LDL, the clearance of nHDL from circulation is not negatively affected by excess cholesterol, which nmay be another reason why HDL, despite being much smaller particle than LDL n(10nm versus 20nm), is not found in atherosclerotic plaques. It’s worth noting, nthat the potential of LPs to become harmful is also influenced by the character nof their lipid constituents. For example, vitamin E and lipids containing nomega-3 fatty acid moieties appear to protect the particles from harmful noxidation and from getting stuck on the walls of blood vessels.

The functional difference between LDL and HDL results nprimarily from the different character of their major apoproteins, apoB-100 and napoA-I, respectively.  ApoB-100, which is found in VLDL, IDL, and LDL, but nnot in HDL, serves as a ligand for LDLR, and provides LDL with the means to ndeliver cholesterol to tissue cells. On the other hand, apoA-I, which is found nexclusively in HDL, has a unique ability to capture and solubilze free ncholesterol. This apoA-I ability enables HDL to act as a cholesterol scavenger.

A mutant apoA-I protein, called apoA-I Milano (apoA-Im), nhas been identified in a group of people that live in a small village inorthern Italy (5). Carriers of this protein, all heterozygous for nthe mutation, had very low levels of HDL (7-14 mg/dl) but showed no clinical nsigns of atherosclerosis (5-7). HDL particles in these subjects were nmarkedly larger than control (12nm versus 9.4nm), which may account for their nimmunity against premature atherosclerosis.  ApoA-Im differs from natural napoA-I by having a cysteine residue at position 173 instead of arginine. This ncysteine residue forms disulfide bridges with other apoA-I molecules or with napoA-II (6, 7), which apparently lead to larger HDL particles. It nalso renders apoA-I more susceptible to catabolism (8), accounting nfor the low HDL levels in apoA-Im carriers.

The therapeutic potential of apoA-I has been recently nassessed in patients with acute coronary syndromes (9). Of the 47 npatients that participated in a randomized controlled trial, 36 received 5 nweekly infusions of recombinant apoA-Im/phospholipid complexes, and 11 received nonly saline infusions. The results showed significant regression in coronary natherosclerotic volume in the apoA-Im treated group, and virtually no change ithe control group (9). These results, if reproduced in larger nclinical trials, may constitute a revolutionary breakthrough in the nnon-invasive treatment of cardiovascular disease. They should also encourage nfurther exploration into the therapeutic usefulness of apoA-Im and normal napoA-I in managing atherosclerotic vascular diseases. 

The lipoproteins – Any of the series of soluble lipid-proteicomplexes which are transported in the blood; each aggregate particle consists nof a spherical hydrophobic core containing triglycerides and cholesterol esters nsurrounded by an amphipathic monolayer of phopholipids, cholesterol and napolipoproteins; classes of lipoproteins include chylomicrons, very low-density nlipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density nlipoproteins (LDL), and high-density lipoproteins (HDL).

chylomicrons – nThe class of largest diameter soluble lipid-protein complexes which the lowest nin density (mass to volume ratio); their composition is ~2% apolipoproteins, n~5% cholesterol, and ~93% triglycerides and phospholipids; their normal role is nto be synthesized by the intestinal mucosal cells to transport dietary n(exogenous) triglycerides and other lipids from the intestines via the lacteals nand lymphatic system to the systemic circulation to the adipose tissue and nliver for storage and use; they are only present in the blood in significant nquantities after the digestion of a meal.

low-density nlipoproteins (LDL) – The class of large diameter nsoluble lipid-protein complexes which the fourth lowest in density (mass to volume nratio); their composition is ~25% apolipoproteins, ~45% cholesterol, and ~30% ntriglycerides and phospholipids; their normal role is to transport cholesterol nand other lipids from the liver and intestines to the tissues for use; elevated nlevels of LDL are associated with increased risk of cardiovascular ndisease.  nickname – bad cholesterol

high-density nlipoproteins (HDL) – The class of small diameter nsoluble lipid-protein complexes which the highest in density (mass to volume nratio); their composition is ~45% apolipoproteins, ~25% cholesterol, and ~30% ntriglycerides and phospholipids; their normal role is to transport cholesterol nand other lipids from the tissues to the liver for disposal; elevated levels of nHDL are associated with decreased risk of cardiovascular disease.

very nlow-density lipoproteins (VLDL) – The class of very large ndiameter soluble lipid-protein complexes which the second lowest in density n(mass to volume ratio); their composition is ~10% apolipoproteins, ~40% ncholesterol, and ~50% triglycerides and phospholipids; their normal role is to ntransport triglycerides and other lipids from the liver and intestines to the ntissues for use; elevated levels of VLDL are associated with some increased nrisk of cardiovascular disease.

formatioof lipoproteins

What nis Cholesterol?

Cholesterol nis a waxy fat found in the body and, despite what you may have been told, is a nnecessary nutrient for the body. Cholesterol is used in the formation of cell nmembranes and plays an important role in hormone, bile and vitamin D nproduction. Cholesterol comes from two sources: the foods that we eat, such as nmeat, dairy products and eggs, and our own liver, which produces about eighty npercent of all the cholesterol in the body. That means that only about twenty npercent of our total cholesterol is obtained from food. Since cholesterol is nnot water-soluble, the liver packages the cholesterol into tiny spheres called nlipoproteins so that the cholesterol can be transported through the blood. The nlipoproteins can be divided into two different categories: low density and high ndensity lipoproteins.

Low density nlipoprotein (LDL): LDL, often dubbed the “bad” ncholesterol, carries most of the cholesterol in the blood and seems to play a nrole in the deposition of fat in arteries. These deposits result in blockages ncalled plaque. In addition to narrowing the narteries and increasing blood pressure, plaque contributes to the hardening of nartery walls, a condition known as atherosclerosis.

High ndensity lipoprotein (HDL): HDL is known as the n”good” cholesterol. HDL carries cholesterol from the blood back to nthe liver for elimination. It is also responsible for removing the plaque nbuildup along the artery walls. Elevated levels of HDL are very desirable nbecause it helps to clear blockages in the arteries, reduces LDL and decreases nblood pressure.