2. CHOLESTEROL ABC

3. CHOLESTEROL “Cholesterol is the most highly decorated small molecule in biology. Thirteen Nobel Prizes have been awarded to scientists who devoted major parts of their careers to cholesterol. Ever since it was isolated from gallstones in 1784, cholesterol has exerted an almost hypnotic fascination for scientists from the most diverse areas of science and medicine…. Cholesterol is a Janus-faced molecule. The very property that makes it useful in cell membranes, namely its absolute insolubility in water, also makes it lethal.” 2

4. 27-C cyclic isoprene unit Derived from acetyl CoA Phenenthrene nucleus OH gp at 3 rd C Double bond at 5 th position Side chain of 8 C at C-17 Methyl gp at C18,19. What is Cholesterol ?

5. Cholesterol is white waxy compound widely distributed in almost all the tissues of the body especially in brain, other nervous tissues, adrenals and liver.

6. Cholesterol Cholesterol is the most abundant steroid in animals - is a precursor for biosynthesis of many other steroids - plants have very small amounts (but have related compounds) - it’s a major component of cell membranes, and affects the fluidity of the membrane due to its bulky structure - the liver synthesizes more cholesterol when dietary intake is low

7. Cholesterol What is it used for? – Lipid bi-layer –half of all cholesterol in our body is in cell membranes – liver uses it to create bile that helps digest fats – Steroid hormones – Vit D Where does it come from? – Diet – eggs, butter, High saturated fat intake etc – Endogenous synthesis – liver makes it

8. Too much cholesterol – Clogs arteries (atherosclerosis) – Causes heart attack or stroke – Formation of gallstones Relation with various diseases like: – Hypertension – Diabetes Mellitus – Thyroid Diseases. – Genetics

9. 8 Complications of long term elevated Cholesterol

10. Desirable Blood Cholesterol Levels The normal LIPID PROFILE Total cholesterolLess than 200 mg/dL LDL ("bad" cholesterol) Less than 100 mg/dL HDL ("good" cholesterol) 40 mg/DL or higher Triglycerides Less than 150 mg/dL

11. What is the difference between Cholesterol and Triglycerides? Triglycerides store unused calories Cholesterol used to build and repair cells High triglycerides are often a sign of obesity and metabolic syndrome High triglycerides can be a sign of poorly controlled type 2 diabetes, low thyroid hormones (hypothyroidism), liver or kidney disease High triglycerides could also be a side effect of taking medications (beta blockers, birth control pills, diuretics, steroids or some chemotherapies). 10

12. Chylomicrons Low density lipoproteins (LDL) High density lipoprteins (HDL) Very low density lipoproteins (VLDL) Cholesterol is too waxy to move through the blood, so it is esterified

13. Proteins and lipids produce particles with distinct densities.

14. Types of Cholesterol HDL considered the 'good' cholesterol Contains a higher level of protein than cholesterol HDLs transport cholesterol from the tissues of the body to the liver, so the cholesterol can be eliminated in the bile. The higher the HDL cholesterol level, the lower the risk of coronary artery disease. LDL considered the ‘bad' cholesterol Higher level of cholesterol than protein LDLs tend to stick to damaged or inflamed areas of blood vessel walls and form plaque buildup The higher the LDL cholesterol level, the higher the risk of coronary artery disease. 13

15. Cholesterol is made from acetyl-CoA Mevalonate formation is the first stage of cholesterol synthesis

16. Overview of cholesterol synthesis © Michael Palmer 2014

17. Transport of cholesterol between the liver and peripheral tissues

18. These particles facilitate transport

19. Regulation of cholesterol biosynthesis HMG-CoA reductase is a major target for regulation. Hormonal regulation by insulin and glucagon Ingestion of cholesterol inhibits endogenous cholesterol synthesis.

20. Cholesterol synthesis is balanced with uptake

21. Cholesterol is taken up by receptor- mediated endocytosis

22. Chylomicrons - Lipoprotein + lipids TG PL Chol ~85% ~9% ~4% released into lymph/blood ~ 50 : 50 ApoC-II activates lipoprotein lipase in capillaries Tissues remove FFA, PL Liver picks up chylomicron remnants

23. Lipoprotein content of the chylomicron changes as it circulates throughout the body - acquiring the apo E & C2 from HDL apoE & apoB-48 are ligands for liver uptake of remnants... Deliver dietary TG and PL to cells dietary CHOL to liver... apoCII is ligand to activate lipoprotein lipase for removal of fatty acids in tissues...

24. apoE is ligand for liver uptake & apoB-100 is ligand for tissue uptake... apoCII is ligand to activate Lipoprotein lipase for removal of fatty acids Delivers endogenous TG and PL to cells... Delivers CHOL to cells...

25. HDL really serves as a circulating resevoir for apoE and apoC’s for efficient removal of LDL’s and lipids from the blood Note that HDL also picks up CHOL from tissues and returns it to the liver for bile synthesis (CHOL excretion pathway) Function of these apoprotein ligands and the cellular receptors that recognize them have important implications for atherosclerosis

26. How can we control cholesterol? Diet: – Minimize sweets and refined carbohydrates (i.e.: white bread, candy). Excess sugar increases triglyceride levels contributing to cholesterol production. – Increase consumption of healthy fats – Consume carbohydrates, with proteins and fats, to slow breakdown. Increases satiety, reduces insulin response – Reduce portion sizes to control calorie intake. helps maintain normal weight and sugar metabolism – Increase Fiber intake

27. How can we control cholesterol? Exercise: – Physical activity increases cellular energy needs – Increases ration of good to bad cholesterol Stress Reduction: – Reduces stress hormone (cortisol) response, reducing blood pressure and blood sugar. Medication and/or supplements

28. Lowering LDL cholesterol: therapeutic principles ● inhibition of cholesterol synthesis ● inhibition of cholesterol uptake ● inhibition of cholesterol ester transfer protein ( ? ) ● inhibition of bile acid reuptake ● LDL apheresis

29. LDL apheresis ● Blood is diverted through an extra-corporeal filtration device ● cells are separated from plasma ● LDL is removed from plasma by filtration ● The remaining plasma and cells are returned to the circulation ● The procedure is repeated in weekly or biweekly intervals

31. Cholesteryl ester transfer protein (CETP), also called plasma lipid transfer protein, is a plasma protein that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins. It collects triglycerides from very-low-density (VLDL) or low-density lipoproteins (LDL) and exchanges them for cholesteryl esters from high-density lipoproteins (HDL), and vice versa.plasmaproteincholesteryl esterstriglycerideslipoproteinsvery-low-densitylow-density lipoproteins high-density lipoproteins