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Disorders of plasma Lipids & lipoproteins

- The major lipids present in the
plasma are:
1) Free fatty acids (FFAs).

3) Cholesterol.

2) Triglycerides (TGs).

4) Phospholipids

-↑ plasma lipids concentrations, particularly cholesterol 
atherosclerosis  cardiovascular disease (coronary, cerebrovascular &
peripheral vascular diseases).
- Management of hypercholesterolemia reduces CVD mortality.
Triglycerides (TGs):
- Consist of glycerol esterified with 3 long-chain FAs  e.g. stearic acid
(18 C atoms) or palmitic acid (16 C atoms).
- Present in dietary fat & synthesized in the liver & adipose tissue.
- Dietary TGs are broken down in small intestine (digestion)  after
absorption TGs are resynthesised in the mucosal cell.
- Stored TGs can be mobilized to provide a source of energy (e.g. In
starvation).
- TGs contain both saturated & unsaturated FAs  such TGs are important
components of cell membranes.

Synthesized mainly in the liver & small intestine.Excreted unchanged in the bile or converted to bile acids  both undergo enterohepatic circulation.Cholesterol: .body can synthesize most of them (except essential FAs = polyunsaturated) .Derived from dietary or tissue TGs.Important component of the cell membrane.Structure similar to TGs but a polar group (e. .has polar part & non-polar part  have detergent properties.Synthesized mainly in the liver  the rate limiting step is catabolised by HMG-CoA reductase.g.Precursor of steroid hormones & bile acids. Phospholipids: . . . . Fatty acids: . . . phosphorylcholine ) replaces one of the 3 FAs. .Is a major component of cell membrane structure. .Present in dietary fat.

FFAs  carried by albumin.Lipid transport in plasma: -Because lipids are not water soluble. . cholesterol & proteins known as apolipoproteins: . . .Lipoproteins = non-polar core of TG & cholesterol esters surrounded by a surface layer of phospholipids. they are transported in plasma in association with protein.other lipids: TGs. cholesterol & phospholipids  circulate in complexes called lipoproteins.

5) HDL  transport cholesterol from extrahepatic tissues to the liver where cholesterol is excreted (reverse cholesterol transport). 4) LDL  cholesterol rich particles formed from IDL by removing more TG & apolipoprotein  it transports cholesterol to extrahepatic tissues.They are classified on the basis of their densities to: 1) Chylomicrons (CM)  the lowest density  transport exogenous fat (mainly TGs) from intestine to the into the circulation  they also transport dietary cholesterol & fat-soluble vitamins to the liver  CMs can not be detected in plasma in the fasting state (>12h after a meal). 2) VLDL  transport endogenous TG synthesized in the liver to the tissues  TG-rich particles. . 3) IDL (intermediate density lipoprotein) formed by removal of TG from VLDL during the transmission from VLDL to LDL  normally its concentration in the plasma is very low (the concentration may increase in pathological disturbances of lipoprotein metabolism).Classification of lipoproteins: .

.Circulating lipoproteins are not static but they are in a dynamic state with continuous exchange of components between the various types.Another classification is according to their electrophoretic mobility: (CM remains at origin) . .

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HDL = high density  It is recognized by specific receptors in peripheral tissues .LPL = lipoprotein lipase. .CM = chylomicron . apoC & apoE).LCAT = lecithin cholesterol acyltransferase .They are separable into 4 main groups (apoA. . . apoB.-Apolipoproteins are a complex family of polypeptides that promote & control the lipid transport in plasma & uptake into tissues. .HTGL = hepatic triglyceride lipase. .

Enzymes involved in lipid transport: 1) LCAT (lecithin cholesterol acyltransferase)  transfers an acyl group (FA residue) from lecithin to cholesterol. forming a cholesterol ester  In plasma. which present on the surface of TG-bearing lipoproteins. 2) Lipoprotein lipase  is attached to tissue capillary endothelium  it splits TGs which present in CMs & VLDL to glycerol & FFAs  its activity increases after a meal. partly as a result of activation of apoC-II. 3) Hepatic TG lipase  its action is similar to that of lipoprotein lipase. 4) Mobilizing lipase  present on adipose tissue cells  controls the release of FAs from adipose tissue to plasma  it is activated by counter-regulatory hormones & inhibited by glucose & insulin. this reactions takes place on HDL & may be stimulated by apoAI. .

CMs are formed from dietary fat in the intestinal mucosa. unesterified cholesterol .CMs are the major transport of exogenous fat  they transport dietary TGs to tissues where they are removed from CMs by the action of lipoprotein lipase.apoA & apoB-48 are synthesized in the gut & present in the newly formed CMs  in the circulation. . the more hydrophilic surface components of CM (apoC. .apoC-II activates lipoprotein lipase  TGs are progressively removed from the hydrophobic cores of CMs  as the size of the CM decreases. CMs transfer apoA to HDL & acquire apoC & apoE from HDL. .Metabolism of plasma lipoproteins: Chylomicron metabolism: . then they enter the lymphatics & reach the systemic circulation via the thoracic duct. skeletal & cardiac muscle and lactating breast  the result of its action will be delivering FFAs form TGs to these tissues where they can be used as energy substrates or re-esterified to TGs for energy storage.Lipoprotein lipase is located on the luminal surface of the capillary endothelium of adipose tissue. .

Most VLDL are formed from TGs synthesized in the liver (endogenous VLDL) but some originates from the intestinal mucosa (exogenous VLDL). .Hepatic synthesis of VLDL is increased whenever there is increased hepatic TGs synthesis (e. VLDL consists mainly of TGs & some unesterified cholesterol. -When first produced.g.Metabolism of VLDL: . When there is increased transport of FFAs to the liver or after a large carbohydrate containing meal). . apoB100 & lesser amount of apoE  then apoC-II is acquired from HDL  then TGs are removed from VLDL in a manner similar to that for CMs  the residual particles (VLDL remnants) are called IDL which either rapidly converted to LDL (more TGs are removed by hepatic TG lipase) or removed from the circulation to the liver.

Metabolism of LDL: .  The size of the intracellular cholesterol pool regulates: a) The rate of cholesterol synthesis through the effect cholesterol on HMGCoA reductase. b) The number of LDL-apoB receptors on the cell surface.LDL is removed from the circulation by 2 processes: one is regulated & one unregulated: 1) Regulated mechanism  involves binding of LDL to specific apoB-100 receptors present on the surface of hepatocytes & other peripheral tissue cells  the entire LDL is incorporated into the cell  inside the cell. they are converted to foam cells (the classic components of atheromatous plaques).LDL is the main carrier of cholesterol (mainly in the form of cholesterol esters which are probably derived from HDL). . .apoB-100 is the only apolipoprotein in LDL. . thereby making unesterified cholesterol available to the cell. LDL fuses with lysosomes  apoB is then broken down & the cholesterol esters are hydrolysed. 2) Unregulated mechanism  receptor-independent cholesterol uptake by the cell (occurs particularly in macrophages)  this mechanism operates when plasma [cholesterol] is increased  uptake of LDL my macrophages is important in the pathogenesis of atherosclerosis  when macrophages become overloaded with cholesterol esters.All LDL is formed from VLDL .

Another function of HDL  it is a source of apoproteins for CMs & VLDL. . .Metabolism of HDL: .Free cholesterol in tissues transfers to HDL in plasma  the cholesterol is then esterified by LCAT & transferred to remnant particles. mainly taken up by the liver (HDL forms the principal route whereby cholesterol can return from peripheral tissues to liver where it can be excreted unchanged in the bile or converted to bile acids. which in turn.HDL is synthesized in the liver & to a lesser extent in the small intestinal mucosa. .HDL particles then undergo complex exchanges of lipid & protein with other plasma lipoproteins. .

At birth.Reference ranges & lab investigations: .2 mmol/L). . . .There is a reverse correlation between HDL cholesterol & CHD risk.6 mmol/L. plasma [cholesterol] is very low (total cholesterol < 2.4-1.2 mmol/L LDL < 3 mmol/L TG (fasting) 0.Normal reference ranges are: Total cholesterol < 5 mmol/L HDL > 1.In the 1st year of life  rapid increase in [cholesterol] (the mean value in childhood is 4. LDL < 1 mmol/L).8 mmol/L . .High plasma [cholesterol] particularly LDL is a major risk factor for CHD.Hypertriglyceridemia is also a risk factor of CHD (women > men) but it is a less important one compared to LDL .

which is particularly associated with type 2 DM. . .N = no significant effect.Plasma TG concentration > 10 mmol/L  increased risk of pancreatitis. is of particular significance  these particles are more atherogenic than other LDL subtypes. .Hypertriglyceridemia due to small dense TG-rich LDL particles (LDL-III). ↓LDL)  after menopause there is no effect. . ..P/S ratio = polyunsaturated / saturated fats in the diet.sex  protection effect in women due to estrogen (↑HDL.

.Plasma lipids should be measured in individuals with the following: 1) CHD 2) Cerebrovascular disease 3) Peripheral vascular disease 4) Family history of premature coronary disease ( age < 60). there may be a pathological disturbance. . .Blood for lipid studies: . .Patients should be on normal diet over 2 weeks prior to blood sampling. Selection of patients for lipid investigations: . CMs should have been cleared  if they are present. hypertension (risk factors for CHD).Lowering plasma [cholesterol] reduces mortality from CHD & risk of stroke. 5) DM. . 6) Patients with clinical features of hyperlipidemia.lipid measurement should be made in all patients known to have vascular disease & in those at increased risk.Alcohol should be stopped on the evening before blood sampling  alcohol is a common cause of hypertriglyceridemia.Blood should be drawn after an overnight fasting (12-14h)  after this time.

2) Secondary hyperlipidemia  acquired disorders  common  management is directed toward the cause: .Disorders of lipid metabolism: 1) Primary hyperlipidemia  genetically determined disorders. secondary cause may coexist & exacerbate the condition.It is always important to exclude secondary causes of hyperlipidemia because even in primary hyperlipidemia. .

Drugs can also exacerbate hyperlipidemia: e. . especially when given to post menopausal women. reduces plasma cholesterol but may cause or exacerbate hypertriglyceridemia.g. β-blockers with intrinsic sympathomimetic activity & α-blockers should be used to treat hypertension in patients with hyperlipidemia.s: Thiazides β-blockers lacking intrinsic sympathomimetic activity. Corticosteroids Immunosuppressants Antiretroviral drugs .Oestrogen..Calcium antagonists. ACE inhibitors. .

patient is rarely survive into adult life.5 mmol/L in adults (LDL > 4.5 mmol/L together with tendon xanthoma in the same person or in a close relative). . .5 – 12 mmol/L/  diagnosis is based on plasma [cholesterol] > 7. .In all cases  defect in the uptake & catabolism of LDL  ↑LDL in . LDL is the affected lipoprotein. .In homozygotes (no functional receptors at all – very rare):  Total [cholesterol] can be as high as 20 mmol/L.  If not treated. .  Patients develop CHD 20 years earlier than general population.mutations can affect LDL receptor synthesis.  develop CHD in childhood.high plasma [cholesterol]. . TG is normal or ↑.Inherited.  Total [cholesterol] = 7. present from childhood.Familial defective apoB-100  mutation in apoB gene decreases the avidity of LDL for its receptors  also causes a similar phenotype.Does not depend upon the presence of environmental factors.In heterozygotes (have around 50% of normal receptor activity): plasma. .Familial hypercholesterolemia: . transport or ligand binding  all cause a similar phenotype.

peripheral & cerebral vascular diseas .Familial dysbetalipoproteinemia (remnant hyperlipoproteinemia): .Occurs due to abnormal conversion of VLDL to LDL that is caused by apoE polymorphism (especially apoE-2/E-2 phenotype)  results in impaired IDL uptake by the liver. .Patients have increased risk of CHD.↑IDL (VLDL remnant) & ↑CM remnants  broad β-band on electrophoresis. .↑total [cholesterol] & ↑TG but ↓LDL.This condition is characterized by cutaneous xanthomas  fat deposits in the palmar creases & by tuberous (‫ )درني‬xanthomata. . .Uncommon. .

Occurs rarely due to lipoprotein lipase deficiency or apoC-II deficiency (required for activation of lipoprotein lipase).g. . recurrent abdominal pain & sometimes hepatosplenomegally. .↑TG & ↑CM concentrations. . .Fasting chylomicronemia.Familial chylomicronemia: .Complications  recurrent pancreatitis. Coconut oil)  these absorbed directly from the gut to blood stream (they do not produce CMs) . .Management  low fat diet (fat restriction)  use TGs with medium chain-length FAs (C8-C11) (e. .present in childhood  eruptive xanthoma.The result will be  failure of CM clearance from the blood stream.

Molecular basis is uncertain  may be due to ↑VLDL synthesis in the liver. .↑VLDL.There is a risk of pancreatitis.↑CMs may also occur. .eruptive xanthoma & lipaemia retinalis (milky appearance of retinal vessels) are usually present.↑TG but not > 5 mmol/L except in obesity or alcohol administration. . . . . .Familial hypertriglyceridemia: .HDL is often reduced.

. . .Hypercholesterolemia due to ↑ HDL only. Familial hyperalphalipoproteinemia: .Either ↑LDL only.Difficult to be classified.↑ risk of CHD.↑ VLDL only or both. . . .Occurs due to hepatic overproduction of apoB  ↑VLDL secretion & ↑ production of LDL from VLDL.Familial combined hyperlipidemia: .No specific treatment is required.Cutaneous manifestations may be present.Reduced risk of CHD. .

treatment is to reduce risk of pancreatitis. . .With severe hypertriglyceridemia.Risk factors for vascular diseases & the rationale for treatment: .The major reason to treat hyperlipidemia is to reduce risk of CVD.The decision to prescribe lipid-lowering treatment should not be based on measurements of lipids alone  some more important risk factors of CVD are: .

exercise & cessation of smoking) & other drugs such as aspirin.Target lipid concentrations  total [cholesterol] < 5 mmol/L. . If patient is at very high risk  total [cholesterol] < 4 mmol/L. .Diet  maintain ideal body weight. βblockers & ACE inhibitors.. . These drugs should be combined with adoption of a healthier lifestyle (diet. LDL < 3 mmol/L.Cholesterol lowering drugs reduce mortality in patients with established CHD. .All patients at risk of CVD  appropriate diet & lifestyle. LDL < 2 mmol/L. not > 30% of energy should be provided by fat (< 1/3 saturated fat).

Ezetimibe  new. more specific. 2) Bile-acid sequestrants  bind with bile acids in the gut  prevent their absorption  interrupt their enterohepatic circulation  ↓hepatic bile acid pool  ↑ conversion of cholesterol into bile acids. Nicotinic acid derivatives (↓VLDL synthesis).Treatment of hypercholesterolemia: 1) Statins (HMG-CoA reductase inhibitors)  the treatment of choice  inhibit cholesterol synthesis  reduced intracellular [cholesterol]  increased LDL receptor expression  reduced plasma LDL.  they also ↑HDL. better tolerated inhibitor of cholesterol absorption. Fibrates.  They also slightly reduce TGs & increase HDL. 3) Treatment of hypertriglyceridemia: 1) 2) 3) 4) Control body weight & any exacerbating factors. 4) Fibrates  stimulate lipoprotein lipase  less effective than statins in reducing cholesterol but more effective at lowering TGs. Fish oil  rich in omega-3-polyunsaturated FAs & also ↓VLDL synthesis .

3) Tangier disease: -) Caused by increased apoA-I catabolism (apoA-I stimulates cholesterol uptake to HDL). . 2) Hypobetalipoproteinemia: -) Partial deficiency of apoB  CM. VLDL & LDL are present but in low concentrations. -) Malabsorption of fat.Lipoprotein deficiency: 1) Abetalipoproteinemia: -) Complete absence of apoB  CM. -) Reduced HDL levels. VLDL & LDL are absent from the plasma. -) Plasma cholesterol & TG concentrations are very low. -) Cholesterol esters accumulate in lymphoreticular system due to excessive phagocytosis of abnormal VLDL & CMs.