CHOLESTEROL & ITS

SIGNIFICANCEPresented byMelbia shiny

First MDSOral medicine & radiology

INTRODUCTION

Light yellow crystalline solid Soluble in chloroform, & fat solvents Distributed in brain ,nerves,

muscle,adipose tissue ,skin ,blood, liver,& spleen.

Absent in plant.

STRUCTURE has cyclopentano

perhydrophenanthrene ring ,A,B,C,D rings are present.

Has 27 carbon atoms. One hydroxyl group on third carbon

atom Double bond between 5&6 C atoms 8 C side chain.

FUNCTION1. Cholesterol is precursor for synthesis

of vitamin D & bile acids .2. Cell membrane- it has modulating

effect on fluid state of membrane.3. Nerve conduction –it is used to insulate

nerve fibers.4. Fatty acids transported to liver as

cholesterol esters for oxidation.

5.Steroid hormones - glucocorticods ,androgene, estrogen are synthesized from cholestrol.

6.Essential ingredient in structure of lipoprotein.

EXCREATION Cholesterol is excreted through bile prior

esterification with PUFA Partly reabsorbed from intestine Unabsorbed portion is acted by

intestinal bacteria to form cholestanol & coprostanol which is excreated as fecal sterols

Another part is converted into bile acids ,excreted as bilesalts.

DEGRADATION OF CHOLESTEROL Synthesis of bile acids

Synthesis of vitamin D cholestrol

7 dehydrocholesterol uv rays cholecalciferol in liver 25 cholecalciferol in kidney(parathromone) 1,25 dehydrocholecalciferol(active vitD)

TRANSPORT OF CHOLESTEROL IN BLOOD Being lipid it is insoluble in water Cholestrol is complexed with protein to

form lipoprotein. Protein part is apolipoprotein LACT(lecithin cholesterol

acyltransferase) is responsible for transport & elimination of cholesterol from body

CLASSIFICATION OF LIPOPROTEIN1. Chylomicrons2. Very low density lipoprotein(VLDL)3. Intermediate density lipoprotein(IDL)4. Low density lipoprotein(LDL)5. High density lipoprotein(HDL)6. Free fatty acids

GENERAL CHARACTERISTICS OF LIPOPROTEIN Lipoprotein have polar periphery made

of proteins (apolipoprotein), phospholipids, & cholestrol.

Inner core consists of hydrophobic TAG & phospholipids

SYNTHESIS OF LIPOPROTEIN Chylomicrons – intestinal mucosal cells VLDL – in liver from glycerol & fatty acid LDL – from VLDL , rich in cholestrol HDL - intestinal cells Free fatty acids – from lipolysis of

triglycerides

METABOLISM OF LIPOPROTEIN Chylomicrons lipoprotein lipase Storage in adipose tissues Remnants taken by liver VLDL Activates lipoproteinlipase taken by

adipose tissue & muscle Remanent is IDL , loses triglycerides,

form LDL Lipoprotein cascade pathway

LDL LDL receptors- clathrin coated pits Receptor-LDL complex internalized by

endocytosis Vesicle fuse with lysosomes Lysosomal enzyme degrade to form free

cholesterol

HDL Intestinal cells – release nascent HDL

(discoid) LACT catalyses esterification of free

cholesterol & transfer to HDL HDL also recieves free cholesterol from

peripheral tissues Apoprotein A promote LACT activity Enter liver & are degraded

FUNCTIONS OF LIPOPROTEIN Chylomicrons- transport of dietary

triglycerides from intestine to adipose tissue for storage.

VLDL – transport of endogenous triglycerides from liver to peripheral tissues for energy

LDL - transport cholesterol from liver to peripheral tissues

HDL – transport of cholestrol from peripheral tissue to liver (reverse cholesterol transport.)

CLINICAL SIGNIFICANCE Atherosclerosis: Deposition of LDL

esp oxidised LDL in the subintimal regions of arteries is atherosclerosis . are taken by macrophages or scavengers – a starting event in atherosclerosis leading to myocardial infarction.

LDL cholestrol is deposited in tissues hence called bad cholestrol.

The hallmark of atherosclerotic plaque are the foam cells (LDL degraded by macrophages get overloaded with cholesterol)

Progression of atherosclerosis atherosclerotic plaque lead to

narrowing of vessel wall when proliferative changes occur .fibrous proliferation is due to liberation of growth factors by macrophages & platelets

Blood flow through narrow lumen is turbulent, so clot is formed which occludes major vessels.

Thrombosis leads to ischemia & finally infarction.

Early stages it is reversible by lowering LDL level

As lesion progresses arterial change become irreversible.

Risk factor for atherosclerosis:1)serum cholesterol level Normal cholesterol level – below

180 mg/dlValue above 240mg/dl need active

treatment2)LDL cholesterol normal – under 130mg/dl above 160mg/dl - risk

3)HDL levelIs inversely related to myocardial infarction is antiatherogenic. above 65mg/dl protect heart diseaseLevel below 40mg/dl – risk of CADTotal cholesterol : HDL cholesterol > 3.5 ,

dangerousLDL : HDL > 2.5 also dangerous4)Apoprotein level apo B : apo A1 is more reliable 0.4 is good , 1.4 risk of CAD

5)Lipoprotein lipase inhibit fibrinolysis > 30mg/dl increases risk6)Smoking nicotine cause lipolysis & increase

acetyl coA & cholesterol synthesis also cause constriction of arteries

7)Hypertension systolic pressure > 160 – risk of

CAD8)Diabetic mellitus absence of insulin activates lipase ,

so production of acetyl coA & finally cholesterol synthesis.

9)Serum triglyceride normal level- 50-150 mg/dl

10)Obesity & sedentary lifePrevention of atherosclerosis1)Reduction of dietary cholesterol egg yolk & meat high cholesterol2)Vegetable oil & PUFA PUFA- esterification of cholesterol omega 3 fatty acid in fish oil decrease

LDL

3)Moderation in fat intake 20 – 25g of oil & 2-3 g of PUFA per

day4)Green leafy vegetable high fiber content- more bowel

motility & reduced reabsorption of bile salts

Sitosterol(plant sterol) decrease cholesterol absorption

5)Avoid sucrose & smoking

6)Exercise moderate – lower LDL & raise HDL7)Hypolipidemic drugs atarvostatin ,lovastatin & simvostatin

(HMGCoA reductase inhibitors)Cholestyramine & colestipol (bile salt

binding drug) – promote synthesis of bile salts & LDL uptake by liver

Clofibrate- increase activity of lipoprotein lipase

8)Antioxidants Decrease oxidation of LDL Vitamine E &C or beta carotene

HYPERCHOLESTEROLEMIA Increase in plasma cholesterol (> 200

mg/dl) Observed in : Diabetics mellitus Hypothyroidism ( myxedema ) Obstructive jaundice Nephrotic syndrome

HYPOCHOLESTROLEMIA

Seen in Hyperthyroidsm Pernicious anaemia Malabsorption syndrome Hemolytic jaundice

DISORDERS OF PLASMA LIPOPROTEIN Inherited disorders of lipoproteins are

primary hyper / hypolipoproteinemias Secondary lipoprotein disorders are due

to some other diseases

HYPERLIPOPROTEINEMIAS

Elevation in one or more lipoprotein Frederickson classification:

Type I Lipoprotein lipase deficiency > chylomicronsType IIa/hyperbetalipoproteinemiadefect in LDL receptorLDL elevated

Type IIb LDL & VLDL elevated Due to overproduction of apo B Type III/broad beta disease > IDL Type IV > VLD Type VChylomicrons & VLDL are elevated

HYPOLIPOPROTEINEMIAS Familial hypobetalipoproteinemia Impaired synthesis of apoprotein B Abetalipoproteinemia Defect in synthesis of apo B Total absence of beta lipoprotein Less absorption of fat & fat soluble

vitamins Familial alpha lipoprotein

deficiency(tangier disease) HDL is absent

OTHER CONDITIONS Xanthomas-deposition of lipids in

subcutaneous tissues Xanthelesma- lipids deposited in

periorbital skin & contain cholesterol Corneal arcus – deposits of lipids in

cornea xanthomatosis - deposition of lipids in

liver , spleen, & flat bone in skullFatty liver- Triglyceride synthesis &

accumulationImpaired lipoprotein synthesis