1. Lipids Functions Defined on the basis of solubility.
Lipids are heterogeneous group of water insoluble (hydrophobic) organic molecules, they are chemically diverse compound but have one feature: water insoluble
Functions
The biological functions of lipids are divers as their chemistry
1. Lipids in form of a bilayer are essential components of biological membranes.
2. Lipids containing hydrocarbon side chains serve as energy stores.
3. Many intra-and intercellular signaling events involve lipid molecules.

2. dietary fats are absorbed in the small intestine
dietary lipids are not digested to any extent in the mouth or stomach in adults.
The rate of action of acid-stable lipase is very slow in adults, because it is active only at neutral pH.
In the duodenum : emulsification of the dietary lipids occurs.
Lipids are insoluble  hydrolysis occurs only at the interfaces  emulsification increase surface area of lipid droplets .
- this occurs by:
1- bile salts act as detergents.
bile salt = bile acid (steroid nucleus) + glycin or taurine.
2- mechanical mixing due to peristalsis  Forming of micelles

3. * Absorption of lipids by intestinal mucosal cells
The primary products of dietary lipid degradation with the bile salts from mixed micelles.
Short and medium chain length F.A don’t need micelles formation to be absorbed (pass directly)
Effect of unsaturated fatty acid on the absorption of Cholesterol !!!!
Hydro-phobic core
hydrophilic
Brush membrane

4. Resynthesis of triacylglycerol and cholesteryl esters by the intestinal mucosal cell

5. Free Fatty acid are transported via albumin
Formation of micelles increase the surface of lipids exposed to the enzymes which is water soluble.
Free Fatty acid are transported via albumin
T.G lipase 2-monogycerol F.A
Cholesterol ester cholesterol

6. Triacylglycerol is hydrolyzed by Hormone sensitive lipase
Free fatty acid are transported to muscle cells carried by Albumin

7. * Cholesterol and other lipids are carried on plasma lipoproteins:
- cholesterol, cholesterol esters and other lipids are essentially insoluble in water. To be moved from one part to another they should carried as plasma lipoprotein.
Plasma lipoproteins
- Macromolecular complexes of lipids and specific proteins called apolipoprotein with a various combination of phospholipids, cholesterol, cholesterol esters and TG.
* Function : to keep the lipid soluble for transporting them between organs and also provide efficient mechanism for delivering their lipid contents to the tissues.

8. Chylomicrons

9. * Composition of plasma lipoproteins
- TG and cholesterol esters are mainly carried by lipoprotein (In the core : TG + cholesterol ester, In the surface : hydrophilic parts of cholesterol, phospholipids and hydrophilic parts of apolipoproteins
Each class of lipoprotein has specific function determined by point of synthesis, lipid composition and apolipoprotein content.
The composition of the circulating lipoproteins is not static. They are in dynamic state with continuous exchange of components between the various types

10. * Size and density of lipoprotein particles
different combinations of lipids and proteins produce different densities
- can be separated by ultra centrifugation.

11. Classification and characteristics of lipoproteins

12. Functions of apolipoproteins
Apolipoproteins : the free form, have several functions, structural component, recognition sites, activators or coenzymes.

13. The composition of circulating lipoproteins are in dynamic state with continuous exchange of components between the various types.
*TG-rich particles
Chylomicrons-exogenous TG
VLDL: endogenous lipids from liver to cells
IDL: normally it is transient intermediate lipoprotein undetectable in plasma, formed during the conversion of VLDL into LDL
These particles, because of their large size reflect light and plasma containing high concentration appears turbid or milky (lipemia), it a turbid plasma sample is left standing for 18 hr at 4°C the larger chylomicrons( lowest density) form a creamy layer on the surface
Lipemia: presence of high amount of TG in plasma and it appears turbid because these particles are large in size so they scatter light

14. * Lipoproteins that contain mostly cholesterol
LDL formed from VLDL
HDL
These lipoproteins of small size do not scatter light, even at high concentration in plasma do not produce lipaemia.
*The small chylomicron remnants are composed mainly of cholesterol, apoB and apoE
Endogenous Lipid pathway
- the liver is the main source of endogenous lipids
These lipids are transported from the liver in VLDL
Plasma taken from a fasting subject contains only LDL, VLDL, and HDL, CM and IDL are not seen in fasting normal subjects.
70% of plasma cholesterol is incorporated in LDL and only 20% in HDL, the measured plasma cholesterol conc. primarily reflects LDL conc. and TG conc. those of VLDL

15. The Exogenous and Endogenous lipid cycle.

16. Metabolism of lipoproteins

17. * Metabolism of Chylomicrons
* The “nascent chylomicron” that released by intestinal mucosal cells contain apo B-48 (unique for chylomicrons) then this nascent chylomicron is rapidly modified receiving apo E and apo C.II from circulating HDL.
* Function: transport dietary TG to adipocysts and muscle and also to transport Cholesterol and lipid soluble vitamin to the liver
* Degradation of chylomicrons
lipoprotein lipase : (activated by apo C.II) hydrolyses TG in these particles into free fatty acids and glycerol.
*Chylomicrons lipoprotein lipase chylomicron remnants (decrease size, increase density)
- apolipoprotein C NOT E is returned to HDL and the remnant is taken up by hepatocytes.
- Receptors of hepatocytes recognize the remnant through apo E  activation of up taking by endocytosis  degradation by lysosomes  release cholesterol.
- The release of cholesterol regulate the cholesterol synthesis in the liver by decrease HMG CoA reductase and also inhibit allosterically this enzyme.
*The small chylomicron remnants are composed mainly of cholesterol, apoB and apoE
The remnants enter to the liver cells (apo E is binds to its receptors)  release chol and degrade proteins
*Dietary TG have been delivered to adipose tissue and muscle and cholesterol to liver
The uptake of Cholesterol remnants, unlike of LDL, is not influenced by the amount of Cho in hepatic cells.

18. * Metabolism of Chylomicrons
- The largest in size and least density of lipoproteins.
- Synthesized in the endoplasmic reticulum of epithelial cells that line the small intestine, then they are packaged in secretary vesicles by Golgi and exported to lymphatic system then enter the blood stream.

19. * Metabolism of very low density lipoprotein (VLDL)
* VLDL : produced in liver and composed mainly of TG and their function to carry lipids from liver to peripheral tissues and are degraded by lipoprotein lipase
VLDL are the principal transport form of endogenous TG TG are removed by lipoprotein lipase (LPL).
- Excess of F.A can be converted into TG in the liver and packaged with specific apolipoprotein to form VLDL.
- Excess CHO can be converted into F A in the liver and  converted into TG  packaged as VLDL
VLDL contain TG , some cholesterol, apo B100, apo CII and apo E
Apo E and some apo CII is transferred from the circulating HDL
* VLDL are transported in the blood from the liver to muscle and adipose tissue.
VLDL lipoprotein lipase free F.A - oxidation (myocytes) OR resynthesis of TG (adipocytes)

20. Metabolism of very low density lipoprotein (VLDL)

21. * Cholesterol that was transferred to HDL is esterified and then is transferred to VLDL which became denser and smaller (IDL)
*Cholesterol esters transfer from HDL to VLDL by cholesterol ester binding protein CEPT in exchange with TG and PL
*Some IDL taken up by liver via LDL receptors
Further TG in IDL is removed by hepatic triglyceride lipase located on the hepatic endothelial cells and IDL is converted into LDL

22. Metabolism of LDL
* LDL are the principal carriers of cholesterol mainly in the cholesterol ester.
* They are formed from VLDL via IDL
-LDL particles have apo B-100, contain less TG, high concentration of cholesterol and cholesterol esters.
- The primary function of LDL is to provide the peripheral tissue with cholesterol by known mechanism called Receptor- mediated endocytosis.
* apo B-100 is recognized by LDL- receptor  internalization and lysosomal degradation with release of free cholesterol
- VLDL contains apo B-100, but can’t bind to LDL receptors. (the conversion of VLDL into LDL)  exposes of the receptor- binding domain of apo B-100
* Fate of cholesterol
- cholesterol that enter the cell can be incorporated into the cell membrane or can be re-esterified by acyl-CoA:cholesterol tansferase (ACAT) for storage as form of cholesterol esters.
* LDL also con be up taken by liver cells mediated by apo E.

23. *Receptor- mediated endocytosis
Cholesterol is delivered from LDL into the peripheral cells.
* LDL receptors deficiency elevation of plasma LDL increase plasma cholesterol.
Peripheral cells uptake cholesterol.

24. How can the body distinguish between the exogenous or endogenous cholesterol
Practically the live can distinguish the particles that carry the cholesterol;
Endogenous: carried by LDL and the uptake of LDL by the liver or other cells is highly regulated.
Exogenous (from diet): carried by chylomicrons, the chylomicron remnants transport dietary cholesterol to the liver.
High level of exogenous cholesterol increase its entrance to the liver  decrease the synthesis of cholesterol and  decrease the synthesis of LDL receptors  decrease the uptake and increase the level of circulating cholesterol.
* Exercises increase the LDL receptors reduce the LDL-cholesterol level
* Estrogens also increase the LDL receptors  reduce the circulating cholesterol level  LDL of female is less than male
* thyroid hormones (T3) has +ve effect on the binding of LDL to its receptors  hypothyroidism is a common cause of Hypercholesterolemia

25. Role of oxidized lipoproteins in plaque formation in arterial wall
Pathogenesis of atherosclerosis
Macrophages derived from monocytes can take up LDL via specific receptors
The uptake will be activated when LDL will be oxidized via non-specific receptors oveloading with CE  foam cells  component of plaques  atherosclerosis

26. Factors influencing plasma LDL concentrations
The plasma LDL concentration (the measured plasma cholesterol concentration), is determined mainly by the rate of uptake by LDL receptors.
*The liver has a central role in cholesterol metabolism because it:
1. Contains most of the LDL receptors
2. Synthesizes most of the endogenous cholesterol
3. Receives cholesterol from the diet and from lipoproteins
4. Is the only organ that can excrete cholesterol from the body in the bile
*The concentration of LDL receptors on hepatic cell surfaces depends on the amount of cholesterol accumulated in the liver cells.
High intracellular cholesterol level  number of receptors is reduced  increase the circulating cholesterol.
*Factors that lead to the accumulation of cholesterol in the liver will, by reducing receptor numbers, increase plasma LDL concentrations.

27. Cholesterol absorption from the intestine is increased if the diet is rich in saturated fat,  efficient micelle formation  chylomicrons  transported to the liver in chylomicron remnant particles that are taken up by chylomicron-remnant receptors.
These receptors are not down regulated as LDL receptors
Inhibition of hepatic cholesterol synthesis, by suppression of the enzyme HMG CoA reductase, may not prevent intracellular accumulation if dietary intake is excessive.
Intracellular cholesterol accumulation leads to a reduction in LDL receptor activity. LDL entry into cells therefore falls and plasma concentrations rise.
Cholesterol can be excreted from the body in bile either as cholesterol or as bile salts. Some bile acids are reabsorbed from the intestinal lumen. Any interruption to the enterohepatic circulation results in an increased conversion of cholesterol to bile acids  reduction in hepatic cholesterol stores  increase in the number of LDL receptors.
*The rate of hepatic LDL receptor synthesis is also increased by estrogens and by thyroid hormones.

28. * Metabolism of HDL
- Synthesized in the liver and small intestine as small, protein- rich particles that contain little cholesterol and no cholesterol esters. (nascent HDL, depleted HDL)
- Contain apo A.I, C.II, C.III and others and
LCAT (lecithin- cholesterol acyl transferase) which is called also
PCAT (phosphatidyl choline- cholesterol acyl transferase)
- LCAT is found at the surface of nascent HDL converts the cholesterol and PL of chylomicron as VLDL remnant to cholesterol esters that forms the core of HDL and formation of mature spherical HDL particle.
- Then the cholesterol rich HDL returns to the liver where the cholesterol is unloaded that can be converted into bile salts.
* Depleted HDL can be pick up cholesterol stored in extra hepatic tissues and carry it to the liver in “ Reverse Cholesterol Transport ” pathway.
Nascent HDL binding cholesterol rich cell passive movement of cholesterol from cell to the HDL goes to the liver.
- up taking of cholesterol from cells by enzyme LCAT and storing of cholesterol ester in the core of HDL.

29. * Metabolism of HDL
*Nascent HDL acquires free cholesterol from extrahepatic cells, chylomicrons and VLDL, the nascent HDL is converted into HDL3.
*Nascent HDL binding cholesterol rich cell  passive movement of cholesterol from cell to the HDL
*The cholesterol is esterified by LCAT and CE is transferred to remnant lipoproteins by cholesteryl ester transfer protein (CETP) in exchange for TG
* apo A is activator for LCAT
*Remnant particles are removed from circulation by the liver
*Cholesterol is excreted in bile as it is or as bile salts
* HDL is taken up by liver. “ Reverse Cholesterol Transport ” pathway

30. Reverse Cholesterol Transport

31. HDL functions 1-HDL as reservoir of apolipoproteins
It act as circulating reservoir of apo C.II that can be transferred to VLDL and chylomicron.
And also takes back the apoprotiens before VLDL remnants and chylomicron remnants are taken by the liver.
2-Up taking of free cholesterol
3-Esterification of free cholesterol into CE by LCAT.
* CE (cholesterol esters) that stored in HDL can be transferred into VLDL and exchanged by TG or PE by CE transfer protein.
VLDL LDL CE is utilized by cells.
* Fate of HDL
- HDL is taken by liver by receptor- mediated endocytosis. And CE are degraded and cholesterol can be repackaged in lipoprotein, converted into bile acids or secreted into bile.
* Role of lipoproteins in heart disease
- high levels of cholesterol increase risk of atherosclerosis
linked to high level of LDL, decrease HDL.

32. Disorders of lipid metabolism
Clinical manifestation of hyperlipidaemia:
Prolonged hyperlipidaemia results in accumulation of lipid in tissues and causes cell damage. Lipids may accumulate in arterial wall, subcutaneous tissue, tendons and cornea
Arterial walls.
-It is the most important manifestation of lipid disorders.
-Cholesterol accumulation and associated cellular proliferation and fibrous tissue formation produces atheromatous plaques.
-Atherosclerosis is due to deformation and obstruction of the artery that may result from calcification and ulceration of plaques.
The small lipoproteins LDL and IDL are atherogenic.

33. Xanthelasma
Soft yellow-orange plaques on the eyelids are lipid deposits under the
periorbital skin and may be associated with high plasma LDL-cholesterol concentrations

34. Tendons
Tendinous Xanthomata and usually on Achilles tendons or the extensor tendons of the hands occur in familial hypercholesterolaemia
Cornea:
Corneal arcus under the age of 40 may be caused by the deposition of lipids and associated with high plasma LDL-cholesterol concentrations.

36. Subcutaneous tissue
The accumulation of lipids in subcutaneous tissue causes xanthomatosis (xanthoma: is a yellow nodule plaque). The nature of the lipid fraction most affected usually determines the clinical appearance:
Eruptive xanthomata are crops of small, itchy, yellow nodules (1-4mm) yellowish-brown papules. They are associated with very high plasma VLDL or chylomicron (triglyceride) concentrations, which disappear if plasma lipid concentrations fall to normal.
Appear over extensors of the elbows and knees, and on the back and buttocks of patients with severe hyperlipidaemia

37. Classification of Disorders of lipid metabolism
Currently there is no satisfactory comprehensive classification of lipoprotein disorders.
In practice, lipoprotein disorders are classified as being:
Primary-when the disorder is not due to an identifiable underlying disease.
Secondary-when the disorder is a manifestation of some other disease.
Primary lipid Disorders:
Genetic classifications: are becoming increasingly complex as different mutations are discovered Familial hypercholesterolaemia (FH), may be due to any of over 500 different mutations of the LDL receptor gene.
*The same genotype can be expressed as more than one phenotype in different individuals. i.e different clinical manifestations (signs and symptoms) in different individuals for the same genetic disorder.
*These manifestations depend on the severity of the case, and on the life style
*Until gene therapy and/or specific substitution therapy become more available, genetic classifications, are unlikely to prove very useful in practice.

38. WHO classification of dyslipidemia: based on Fredrickson work and it is phenotypic classification based on the observation pattern of lipoprotein abnormality
*The Fredrickson or World Health Organization classification is the most widely accepted for the primary hyperlipidaemias.
* It is based the appearance of fasting plasma sample after standing for 12 hr at 4°C and analysis of its cholesterol and TG
* As a result, patients with the same genetic defect may fall into different groups, or may change grouping as the disease progresses or treated.
* The major advantage of this classification is that it is widely accepted and gives some guidance for treatment
*The six types by Fredrickson are not equally common. Type I and V are rare, while types IIa, IIb and IV are very common.

39. Fredrickson (WHO) classification of dyslipidaemia

40. Fredrickson (WHO) classification of dyslipidaemia

41. Genetic classifications:
Risk
Fredrickson
Genetic defect
Disease
CHD
IIa or IIb
Reduced number of functional LDL receptors
Familial Hypercholesterolemia
IV or V
Possibly single gene defect
Familial hypertriglyceridemia
IIa, IIb, IV or V
Familail combined hyperlipidemia
Pancreatitis I
Reduced levels of functional LPL
Lipoprotein lipase deficiency
Inability to synthesize apo C-II (cofactor of LPL)
Apo C-II deficiency
Fat soluble vitamins deficiencies, neurological deficit
Normal
Inability to synthesize apo B
Abetalipoproteinemia
Neurological deficit, CE storage in abnormal places
Inability to synthesize apo A
Analphalipoproteinemia

42. Predominant hypercholesterolaemia
The risk of developing cardiovascular disease increases as the plasma cholesterol concentration rises above 200 mg/dl in the absence of other risk factors this value could be raised
Causes of hypercholesterolaemia
- Hypercholesterolaemia associated with little or no elevation of plasma triglyceride concentration is almost always due to a raised plasma LDL
*The coexistence of an underlying genetic defect or other lipid disorders cause a greater increase in plasma cholesterol with age.
Secondary hypercholesterolaemia.
Disorders that may produce a secondary increase in plasma total and LDL-cholesterol
-primary hypothyroidism,
-diabetes mellitus,
-nephrotic syndrome,
-cholestasis
-drugs (e.g.; thiazides).

43. Primary hyperlipidaemias
Familial hypercholesterolaemia (FH)
* This condition is characterized by high plasma cholesterol concentrations which are present from early childhood and do not depend upon the presence of environmental factors
* Different mutations can affect LDL synthesis, transport, ligand binding, and recycling but all cause a similar phenotype.
*The familial incidence of hypercholesterolaemia, often associated with an increased risk of ischemic heart disease, suggests an inherited disorder.
* Environmental and dietary factors may determine the expression of the defect.
* The risk of developing cardiovascular disease is higher than normal, compared with an age- and sex matched population.

44. Familial (monogenic) hypercholesterolaemia
Caused by a LDL receptor defect  reduced cellular uptake of LDL, particularly by the liver  causes an increase in plasma total and LDL- cholesterol concentrations.
Plasma triglyceride concentrations are either normal or only slightly increased it is the most lethal of the inherited disorders.
In homozygotes LDL
receptors are virtually absent and plasma LDL-cholesterol is 3 to 4 times higher than those in normal subjects patients usually die before the age of 20 from ischaemic heart disease.
In heterozygotes
The number of LDL receptors is reduced by 50% and the plasma cholesterol concentrations are about twice those in normal subjects. They have a 10 to 20-fold higher risk of developing ischaemic heart disease than normal

45. Predominant hypertriglyceridaemia
* Elevated plasma triglyceride concentrations may be due to an increase in plasma VLDL, or chylomicrons or both.
* Sustained and very high plasma concentrations of chylomicrons are associated with abdominal pain and even acute pancreatitis, as well as eruptive xanthomata.
* Many cases of hypertriglyceridaemia are symptom free. These large lipoproteins are unlikely to cause artheroma, per se. However, many patients with increased concentrations of VLDL-triglyceride have reduced concentration of plasma HDL and increased plasma concentration of LDL or IDL, which contain cholesterol.
* Hypertriglyceridaemia is usually secondary to another disease: obesity and excessive carbohydrate intake, alcohol, drugs (thiazide diuretics) and acute pancreatitis).

46. Familial endogenous hypertriglyceridaemia is caused by hepatic triglyceride overproduction with increased VLDL secretion.
* The condition usually becomes apparent only after the fourth decade.
* It may be associated with: obesity, glucose intolerance, decrease in plasma HDL-cholesterol concentration and hyperuricaemia.
* Insulin resistance may be a common factor in the above conditions.
* High plasma triglyceride concentrations may cause eruptive xanthomata.
* primary hypertriglyceridaemia is less than primary hypercholesterolaemia

47. Familial combined hyperlipidaemia: Mixed hyperlipidaemia
It is common disorder
Associated with excessive hepatic production of apoB,  increase LDL and VLDL-triglyceride synthesis due to either a primary or secondary disorder.
Family members have a variety of different phenotypes.
In one-third there is an increase in plasma LDL-cholesterol
In another third there is an increase in both LDL-cholesterol and VLDL-triglycerides
The remaining third have VLDL-hypertriglyceridaemia.
The lipid abnormalities appear significantly in the after the age 30
The risk of ischaemic heart disease in all cases is higher
Raised plasma concentrations of both cholesterol and triglycerides are commonest in patients with poorly controlled diabetes mellitus, severe hypothyroidism or the nephrotic syndrome.

48. Hyperchylomicronaemia
* is usually due either to an acquired or inherited deficiency of lipoprotein lipase.
* Insulin is needed for optimal enzyme activity  hyperchylomiconaemia may occur in poorly controlled diabetic patients.
Inherited lipoprotein lipase deficiency may be due to:
A) True deficiency of the enzyme
B) Reduced activity of the enzyme because of apo C-II deficiency. Which is an activator for lipoprotein lipase
The plasma is very turbid because of the accumulation of chylomicrons.
True lipoprotein lipase deficiency usually presents during childhood, with signs and symptoms due to an excess of fat at skin, liver (hepatomegaly) retinal vessels and abdomen.
Hyperchylomiconaemia due to apoC-II deficiency is most likely to present in adults.

49. Rare disorders associated with lipid metabolism
A few rare disorders, which are associated with reduced plasma lipid concentration but with the accumulation of lipid in tissues
Inherited disorder of HDL deficiency (Tangier disease):
Called also Analphalipoproteinaemia
Associated with premature coronary heart disease.
An abnormal apoA leads to an increased rate of catabolism of HDL.
Plasma HDL concentrations are low and cholesterol esters accumulate in the reticuloendothelial system.
Abetalipoproteinaemia (ApoB deficiency):
- absence of Apo B
- results in impaired synthesis of chylomicrons and VLDL, and therefore of LDL.
lipids cannot be transported from the intestine to the liver.
risk: decrease in fat soluble vitamins  lead to neurological defects, for treatment vitamins are given I. V is given
Hypobetalipoproteinaemia
In this condition there is partial deficiency of apo B; CM, VLDL and LDL are present, but in low concentrations.
LCAT deficiency:
results in accumulation of free, mostly unesterified, cholesterol in tissues

50. Secondary lipid disorders
Secondary hyperlipoproteina is a well recognized feature of a number of diseases
Common causes of secondary hyperlipidaemia including obesity and diabetes mellitus.
Management should be directed towards the cause.

51. Fatty acid  TG  VLDL Effect of Alcohol on Lipid profile
Large quantity of Ethanol increases the synthesis of Fatty acid, because of production of NADH and acetate
Fatty acid  TG  VLDL
Ethanol
Acetaladehyde
Acetate
Alcohol dehydrogenase
Aldehyde dehydrogenase
NADH

52. Lipoprotein metabolism in diabetes mellitus
Insulin has a major role in the control of fat metabolism. Both type I and type 2 DM are associated with abnormalities of plasma lipids
In uncontrolled type I DM
* Marked hypertriglyceridaemia, increase in VLDL and often chylomicronaemia as a result of decreased activity of lipoprotein lipase and increased activity of hormone-sensitive lipase  leading to increased flux of free fatty acids from adipose tissue  that act as a substrate for hepatic triglyceride synthesis VLDL synthesis and accumulation  increase LDL.
* Both VLDL and chylomicrones need insulin for optimum catalysis.
The degree of hypertriglyceridaemia correlates well with glycaemic control and insulin treatment can reverse the hypertriglyceidaemia.
* LDL can also be increased, and HDL is decreased.
*The VLDL contains increased triglyceride and cholesteryl ester in relation to the amount of apolipoptotein
* Glycation of apolipoprotein B may enhance the atherogenicity of LDL by reducing its affinity for the LDL receptor, so leading to increased uptake by macrophage scavenger receptors.
* Treatment with lipid-lowering drugs may be appropriate, to reduce the risk of vascular disease

53. Investigation of lipid disorders
Plasma sampling
Plasma lipid concentrations and lipoprotein patterns are affected by eating, smoking, alcohol intake, stress and changes in posture.
It is essential that the samples are taken under standard conditions. The following points are important:
1) Plasma cholesterol concentrations are not significantly affected after a fatty meal while plasma triglyceride concentrations are affected. Therefore, specimens for analysis of both should be taken after the patient has fasted for 12 hours.
2) The patient should be taking a 'normal' diet and his weight should have remained constant for about two weeks before the tests.
3) Unless treatment is being monitored, the patient must not be on any drugs designed to lower plasma lipid concentrations

54. Investigation of lipid disorders
Plasma sampling
3) Unless treatment is being monitored, the patient must not be on any drugs designed to lower plasma lipid concentrations
4) Lipoprotein concentrations, like those of all large particles, are affected by venous stasis and posture. A standardized collection procedure is important if serial estimations to assess the effect of treatment are used.
5) Stress may affect plasma lipid concentrations like myocardial infarct, major operation, or any serious illness.
6) The blood sample should not be heparinized and plasma or serum must be separated from cells as soon as possible

55. Lipid profile
LDL-cholesterol is most commonly estimated from quantitative measurements of total and HDL-cholesterol and plasma triglycerides (TG) using the empirical relationship of Friedewald et al. (1972)
[LDL-chol] = [Total chol] - [HDL-chol] - ([TG]/5) where all concentrations are given in mg/dL
The ([TG]/5) is used as an estimate of VLDL-cholesterol concentration. It assumes, first, that virtually all of the plasma TG is carried on VLDL, and second, that the TG:cholesterol ratio of VLDL is constant at about 5:1 (Friedewald et al. 1972).
Neither assumption is strictly true.
Limitations of the Friedewald equation: The Friedewald equation should not be used under the following circumstances:
When chylomicrons are present.
When plasma triglyceride concentration exceeds 400 mg/dL (4.52 mmol/L). In circumstances in which these conditions apply, LDL-cholesterol should be measured directly.

56. Reference ranges and laboratory investigation
Plasma conc at birth is very low (total chol less than 100 mg/dL 2.6 mmol/L) and there is rapid increase in in first year of life
Elevated plasma chol is a major risk factor for CHD
There are many CHD risk factors
Smoking will increase the risk factor
There is an inverse correlation between HDL cholesterol and CHD risk.
So it is inappropriate to define a reference range for plasma chol concentration.
But it is preferable to consider an individual person's chol concentration taking in consideration all other CHD risk factors

57. Coronary Heart Disease Risk Factors Determined By The NCEP (National Cholesterol Education Program) and Adult Treatment Panels

58. Positive Risk Factors
Age:  45 years for men;  55 years or premature menopause for women
Family history of premature CHD
Current cigarette smoking
Hypertension (BP  140/90 mmHg or taking antihypertensive medication)
LDL cholesterol concentration  160 mg/dL ( 4.1mmol/L), with ≤ 1 risk factor
LDL cholesterol concentration  130 mg/dL (3.4 mmol/L), with ≤ 2 risk factors
LDL cholesterol concentration  100 mg/dL (2.6 mmol/L), with CHD or risk equivalent
HDL cholesterol concentration < 40 mg/dL (< 1.0 mmol/L)
Diabetes mellitus = CHD risk equivalent
Negative Risk Factors
HDL cholesterol concentration  60 mg/dL ( 1.6 mmol/L)
LDL cholesterol < 100 mg/dL (2.6 < mmol/L)

59. 3. A low HDL level (less than 40 mg/dL [men] or 50 mg/dL [women])
Multiple metabolic risk factors
A diagnosis of metabolic syndrome is made if a patient has three or more of the following:
Abdominal obesity (a waist circumference of more than 40 inches [men] or 35 inches [women])
2. An elevated triglyceride level (150 mg/dL or higher)
3. A low HDL level (less than 40 mg/dL [men] or 50 mg/dL [women])
4. A high-normal or high blood pressure level (130/85 mm Hg or higher)
5. A high fasting glucose level (110 mg/dL or higher)

60. 6 3 3 2 14
Means 20 of 100 people with this level of risk will have a heart attack in the next 10 years.

61. Risk Assessment Tool for Estimating Your 10-year Risk of Having a Heart Attack
10-Year Risk Calculator
10-Year Risk Calculator Results

62. Risk Factor Intervention
Target treatment based on risk
High: 10 year risk > 20%
Intermediate: 10 year risk 10 –20%
Low: 10 year risk < 10%
• Preventive strategies differ depending on risk category
Aspirin
Cholesterol lowering
Risk Level LDL Goal (mg/dl) Consider Drug Therapy ___________________________________________________
High
> 20% < ≥100
Intermediate
10 –20% < ≥160
Low
< 10% < ≥190

63. The End

64. Drugs: Thiaziade diuertics and b-blockers  hypertriglyceridaemia since these drugs affect the homeostasis of K+ and Na+ which is important for the conversion of proinsulin into insulin
low insulin levels  similar events of diabetes
Hypothyrodism  low of T3, T4  decrease the uptake of LDL by the LDL-receptor mediated mechanism
Nephrotic syndrome: increase the cholesterol level
NS is associated with loss of protein with the urine 
This will trigger the body to increase the synthesis of protein including Apo B and other lipoproteins which lead to increase the cholesterol
Also may be due to loss of proteins responsible for regulation of lipid metabolism

65. * Metabolism of Chylomicrons
*Esterified cholesterol is transferred to the CM remnants from HDL, in exchange for triglyceride, by cholesteryl ester transfer protein
*CM remnants depleted from TG and enriched in CE and taken up by liver

66. As the VLDL particles become smaller, PL, free cholesterol and apolipoproteins are released from VLDL and taken up by HDL  converting the VLDL into IDL