LIPOPROTEINS Because lipids are relatively insoluble in aqueous media, - PowerPoint Presentation

1. LIPOPROTEINSBecause lipids are relatively insoluble in aqueous media,They bind with soluble protein complexes called lipoproteinsLipids can be derived from food (exogenous) or synthesizedin the body (endogenous). The water-soluble (polar)groups of proteins, phospholipids and free cholesterolface outwards and surround an inner insoluble (nonpolar)core of triglyceride and cholesterol esters.Lipoproteins are classified by their density,which inversely reflects their size. The greater the lipidto protein ratio, the larger their size and the lower thedensity. Lipoproteins can be classified into five mainGroups are transported in body fluids as, often spherical,

2. Chylomicrons are the largest and least denselipoproteins and transport exogenous lipid from theintestine to all cells. Very low-density lipoproteins (VLDLs) transportendogenous lipid from the liver to cells. Intermediate-density lipoproteins (IDLs), whichare transient and formed during the conversion ofVLDL to low-density lipoprotein (LDL), are notnormally present in plasma.The other two lipoprotein classes contain mainlycholesterol and are smaller in size: Low-density lipoproteins are formed from VLDLsand carry cholesterol to cells. High-density lipoproteins (HDLs) are the mostdense lipoproteins and are involved in the transportof cholesterol from cells back to the liver (reversecholesterol transport). These lipoproteins can befurther divided by density into HDL2 and HDL3.

3. If a lipaemic plasma sample, for example after ameal, is left overnight at 4°C, the larger and less densechylomicrons form a creamy layer on the surface. Thesmaller and denser VLDL and IDL particles do not rise,and the sample may appear diffusely turbid. The LDLand HDL particles do not contribute to this turbiditybecause they are small and do not scatter light. Fastingplasma from normal individuals contains only VLDL,LDL and HDL particles.In some cases of hyperlipidaemia, the lipoproteinpatterns have been classified (Fredrickson’sclassifi cation) according to their electrophoreticmobility. Four principal bands are formed, based ontheir relative positions, by protein electrophoresis,namely α (HDL), pre-β (VLDL),β(LDL) andchylomicrons

4. Intermediate-density lipoproteins in excess mayproduce a broad b-band. Some individuals withhyperlipidaemia may show varying electrophoreticpatterns at different times.Ultracentrifugation (separation based upon particle density) or electrophoretic techniquesare rarely used in routine clinical practice as thesemay require completed apparatus and experiencedoperators. Instead, the lipoprotein compositionof plasma may be inferred from standard clinicallaboratory lipid assays. As fasting plasma does notnormally contain chylomicrons, the triglyceridecontent reflects VLDL. Furthermore, generally about70 per cent of plasma cholesterol is incorporated asLDL and 20 per cent as HDL. The latter particles,because of their high density, can be quantifiedby precipitation techniques that can assay theircholesterol content by subtraction, although directHDL assays are now often used.

5. Lipoprotien has been found. similar in lipid compositionto LDL but has a higher protein content. One of itsproteins, called apolipoprotein (a), shows homology toplasminogen and may disrupt fibrinolysis, thus evokinga thrombotic tendency. The plasma concentration ofLp(a) is normally less than 0.30 g/L and it is thought tobe an independent cardiovascular risk factor.The proteins associated with lipoproteins are calledapolipoproteins (apo). ApoA (mainly apoA1 and apoA2)is the major group associated with HDL particles. TheapoB series (apoB100) is predominantly found withLDL particles and is the ligand for the LDL receptor.Low-density lipoprotein has one molecule of apoB100per particle. Some reports have suggested that theplasma apoA1 to apoB ratio may be a useful measure ofcardiovascular risk (increased if the ratio is less than 1)and it is not significantly influenced by the fasting statusof the patient. The apoC series is particularly importantin triglyceride metabolism and, with the apoE series,freely interchanges between various lipoproteins.

6. Lipoprotein-associated phospholipase A2 [alsocalled platelet-activating factor acetylhydrolase (PAFAH)]is present mainly on LDL and to a lesser degreeHDL. It is produced by inflammatory cells and isinvolved in atherosclerosis formation and levels areassociated with increased risk of coronary arterydisease and stroke.High-density lipoproteinThe transport of cholesterol from non-hepatic cellsto the liver involves HDL particles, in a process calledreverse cholesterol transport . The HDL issynthesized in both hepatic and intestinal cells andsecreted from them as small, nascent HDL particlesrich in free cholesterol, phospholipids, apoA and

7. apoE. If the plasma concentration of VLDL orchylomicrons is low, apoC is also carried in HDL, butas the plasma concentrations of these lipoproteins rise,these particles take up apoC from HDL. In addition,HDL can be formed from the surface coat of VLDLand chylomicrons. Various factors control the rate ofHDL synthesis, including oestrogens, thus explainingwhy plasma concentrations are higher in menstruatingwomen than in menopausal women or men.The enzyme lecithin–cholesterol acyltransferase(LCAT) is present on HDL and catalyses theesterifi cation of free cholesterol and is activated byapoA1, the predominant apolipoprotein of HDL.Some HDL particles also contain apoA2. Most of thisesterified cholesterol is transferred to LDL, VLDLand chylomicron remnants and thus ultimatelyreaches the liver. Some may be stored within the coreof the HDL particle and taken directly to the liver.Cholesterol ester transfer protein (CETP) is involvedin these processes.

8. High-density lipoprotein cholesterol iscardioprotective not only because of the reversecholesterol transport system, which helps to removecholesterol from the peripheral tissues, but alsobecause of the mechanisms that include increasedatherosclerotic plaque stability, protection of LDL fromoxidation, and maintaining the integrity of the vascularendothelium.A plasma HDL cholesterol concentration of lessthan 1.0 mmol/L increased cardiovascular riskand can be raised by various lifestyle changes, such assmoking cessation, regular exercise and weight loss.The fibrate drugs or nicotinic acid are sometimes usedif these measures fail . A low HDL cholesterolconcentration is associated with diabetes mellitus type

9. Chylomicron syndromeThis can be due to familial lipoprotein lipase deficiency,an autosomal recessive disorder affecting about 1 in1 000 000 people. Lipoprotein lipase is involved in the exogenous lipoprotein pathwayby hydrolysing chylomicrons to form chylomicronremnants, and also in the endogenous pathway byconverting VLDL to IDL particles.Presentation as a child with abdominal pain (oftenwith acute pancreatitis) is typical. There is probably noincreased risk of coronary artery disease. Gross elevationof plasma triglycerides due to the accumulationof un cleared chylomicron particles occurs , Lipid stigmata include eruptive xanthomata,hepatosplenomegaly and lipaemia retinalis Other variants of the chylomicrone syndromeinclude circulating inhibitors of lipoprotein lipase apo C3and deficiency of its physiological activator apoC2.Apolipoprotein C2 deficiency is also inherited as anautosomal recessive condition affecting about 1 in1 000 000 people.

10. Treatment of the chylomicron syndrome involvesa low-fat diet, aiming for less than 20 g of fat a day, ifpossible, although compliance on such a diet may bedifficult. Some clinicians supplement the diet withmedium-chain triglycerides and also give 1 per cent ofthe total calorie intake as linoleic acid.In cases of apoC2 deficiency, fresh plasma maytemporarily restore plasma apoC2 levels. To conf rmthe diagnosis of familial lipoprotein lipase deficiency,plasma lipoprotein lipase can be assayed after theintravenous administration of heparin, which releasesthe enzyme from endothelial sites. The assay iscomplicated in that other plasma lipases (hepatic lipaseand phospholipase, for example) contribute to theoverall plasma lipase activity. Inhibition of lipoproteinlipase can be performed using protamine, high salineconcentrations or specific antibodies and its overallactivity can be calculated by subtraction.If apoC2 deficiency is suspected, the plasmaconcentrations of this activator can be assayed.

11. Familial hypercholesterolaemiaThis condition is usually inherited as an autosomaldominant trait and was described by Goldstein andBrown. The inheritance of one mutant gene thatencodes for the LDL receptor affects about 1 in every500 people (more common in certain groups suchas Afrikaners and French Canadians), resulting inAt least five types of mutation of the LDL receptorhave been described, resulting in reduced synthesis,failure of transport of the synthesized receptor to theGolgi complex within the cell, defective LDL binding orinadequate expression or defective recycling of the LDLreceptor at the cell surface.familial hypercholesterolaemia (FH) is defined asa plasma cholesterol concentration of more than7.5 mmol/L in an adult (more than 6.7 mmol/L inchildren under 16 years) or a plasma LDL cholesterolconcentration of more than 4.9 mmol/L in an adultin the presence of tendon xanthoma. plus a family history of either an elevated plasmacholesterol concentration of more than 7.5 mmol/L ina fi rst-degree or second-degree relative or myocardialinfarction below the age of 50 years in a fi rst-degree

12. relative or below the age of 60 years in a second-degreerelative.Typically, patients manifest severe hypercholesterolaemia,with a relatively normal plasma triglycerideconcentration in conjunction with xanthomata, whichcan affect the back of the hands, elbows, Achilles tendonsor the insertion of the patellar tendon into the pretibialtuberosity . Premature cardiovasculardisease is often observed, along with premature corneal arc

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15. The diagnosis of FH is usually obvious from themarkedly elevated plasma cholesterol concentrationand the presence of tendon xanthomata in the patient orfirst-degree relation. The diagnosis may not be so clearcut in patients without the lipid stigmata. A functionalassay of the LDL receptors has recently been describedusing cultured lymphocytes, but this has not yet gainedwide routine acceptance.Homozygous FH can be very severe. There is aconsiderable risk of coronary artery disease, aorticstenosis and early fatal myocardial infarction beforethe age of 20 years. Florid xanthoma occurs inchildhood including tendon, planar and cutaneoustypes. Atheroma of the aortic root may manifest beforepuberty, associated with coronary ostial stenosis.

16. Familial defective apoB3500This condition is due to a mutation in the apoB generesulting in a substitution of arginine at the 3500 aminoacid position for glutamine. Apolipoprotein B is theligand upon the LDL particle for the LDL receptor. Itmay be indistinguishable clinically from FH and is alsoassociated with hypercholesterolaemia and prematurecoronary artery disease. The treatment is similar to thatfor heterozygote FH.

17. Familial combined hyperlipidaemiaIn familial combined hyperlipidaemia (FCH), the plasmalipids may elevated, plasma cholesterol concentrationsoften being between 6 mmol/L and 9 mmol/L and plasmatriglyceride between 2 mmol/L and 6 mmol/L. The Familial combined hyperlipidaemia maybe inherited as an autosomal dominant trait . About 0.5 per cent of the Europeanpopulation is affected, and there is an increasedincidence of coronary artery disease in family members.

18. metabolic defect is unclear, although plasma apoBis often elevated due to increased synthesis; LDL andVLDL apoB concentration is increased. The synthesis ofVLDL triglyceride is increased in FCH and there mayalso be a relationship with insulin resistance.The diagnosis of FCH is suspected if there is afamily history of hyperlipidaemia, particularly if familymembers show different lipoprotein phenotypes. Thereis often a family history of cardiovascular disease.However, the diagnosis can be difficult and it sometimesneeds to be distinguished from FH (xanthomataare not usually present in FCH) and familialhypertriglyceridaemia

19. Familial hypertriglyceridaemiaFamilial hypertriglyceridaemia is often observed with lowHDL cholesterol concentration. The condition usuallydevelops after puberty and is rare in childhood. The exactmetabolic defect is unclear, although overproduction ofVLDL or a decrease in VLDL conversion to LDL is likely.There may be an increased risk of cardiovascular disease.Acute pancreatitis may also occur, and is more likelywhen the concentration of plasma triglycerides is morethan 10 mmol/L. Some patients show hyperinsulinaemiaand insulin resistance. Dietary measures, and sometimeslipid-lowering drugs such as the fibrates or w-3 fattyacids, are used to treat the condition

20. Type III hyperlipoproteinaemiaThis condition is also called familial dysbetalipoproteinaemiaor broad b-hyperlipidaemia. The underlying biochemical defect is one of a reduced: clearance of chylomicron and VLDL remnants. Thename broad b-hyperlipidaemia is sometimes usedbecause of the characteristic plasma lipoproteinelectrophoretic pattern that is often observed (thebroad b-band that is seen being remnant particles).The mechanism for the disorder seems to be thatapoE2-bearing particles have poor binding to theapoB/E (remnant) receptor and thus are not effectively cleared from the circulation.

21. A concurrent increasein plasma VLDL concentration also seems necessaryfor the condition to be expressed, such as might occurin diabetes mellitus, hypothyroidism or obesity. Somepatients may show either an autosomal recessive or adominant mode of inheritance of the condition.The palmar striae (palmar xanthomata) areconsidered pathognomonic for the disorder, buttuberoeruptive xanthomata, typically on the elbows andknees, xanthelasma and corneal arcus have also beendescribed in this condition. Peripheral vascular diseaseis a typical feature of this hyperlipidaemic disorder, asis premature coronary artery disease.Plasma lipid determination frequently revealshypercholesterolaemia and hypertriglyceridaemia,often in similar molar proportions with plasmaconcentrations of around 9–10 mmol/L. Plasma HDLcholesterol concentration is usually low. Plasma LDLconcentration may also be low due to the fact that thereis reduced conversion from IDL particles, although itmay also be normal or elevated.

22. Polygenic hypercholesterolaemiaThis is one of the most common causes of a raisedplasma cholesterol concentration. This condition isthe result of a complex interaction between multipleenvironmental and genetic factors. In other words, itis not due to a single gene abnormality, and it is likelythat it is the result of more than one metabolic defect.There is usually either an increase in LDL productionor a decrease in LDL catabolism. The plasma cholesterol concentrationis usually either mildly or moderately elevated. Animportant negative clinical finding is the absence oftendon xanthomata, the presence of which would tendto rule out the diagnosis. Usually less than 10 per cent offirst-degree relations have similar lipid abnormalities,compared with FH or FCH in which about 50 per centof first-degree family members are affected. There mayalso be a family history of premature coronary arterydisease. Individuals may have a high intake of dietaryfat and be overweight.

23. HyperalphalipoproteinaemiaHyperalphalipoproteinaemia results in elevatedplasma HDL cholesterol concentration and can beinherited as an autosomal dominant condition or, insome cases, may show polygenic features. The totalplasma cholesterol concentration can be elevated,with normal LDL cholesterol concentration. There isno increased prevalence of cardiovascular disease inthis condition; in fact, the contrary probably applies,with some individuals showing longevity. Plasma HDLconcentration is thought to be cardioprotective .

24. PrimaryHyperalphalipoproteinaemiaCholesterol ester transfer protein deficiencySecondaryHigh ethanol intakeExerciseCertain drugs, e.g. estrogens, fibrates, nicotinic acid,statins, phenytoin, rifampicinSome causes of raised plasmahigh-density lipoprotein (HDL) cholesterol

25. PrimaryFamilial hypoalphalipoproteinaemiaApoA1 abnormalitiesTangier’s diseaseLecithin–cholesterol acyltransferase (LCAT) deficiencyFish-eye diseaseSecondaryTobacco smokingObesityPoorly controlled diabetes mellitusInsulin resistance and metabolic syndromeChronic kidney diseaseCertain drugs, e.g. testosterone, probucol, b-blockers without intrinsic sympathomimetic activity) ,progestogens, anabolic steroids, bexaroteneCauses of low plasma highdensitylipoprotein (HDL) cholesterol

26. Some important causes of secondary hyperlipidaemiaPredominant hypercholesterolaemiaHypothyroidismNephrotic syndromeCholestasis, e.g. primary biliary cirrhosisAcute intermittent porphyriaAnorexia nervosa/bulimiaCertain drugs or toxins, e.g. ciclosporin andchlorinated hydrocarbonsPredominant hypertriglyceridaemiaAlcohol excessObesityDiabetes mellitus and metabolic syndromeCertain drugs, e.g. estrogens, b-blockers (withoutintrinsic sympathomimetic activity), thiazide diuretics,acitretin, protease inhibitors, some neuroleptics andglucocorticoidsChronic kidney diseaseSome glycogen storage diseases, e.g. von Gierke’stype ISystemic lupus erythematosusParaproteinaemia