1. Lecture 14 Lipoprotein and Cholesterol Metabolism

2. Delivery of Fat to Tissues Chylomicrons interact with tissues through lipoprotein lipase (LPL) LPL is on the surface of cells Fat in chylomicrons hydrolysed to fatty acids and glycerol Insulin stimulates LPL Also increases the supply of glycerol 3-phosphate for re-esterification

3. Fate of FAs and Chylomicrons Fatty acids from chylomicron after lipolysis can be: –Burnt in the heart and muscle –Stored in WAT (hopefully not elsewhere) NB. Build up of fat in the muscle in Type 2 diabetes FAs in WAT mainly re-esterified  FAT –Re-esterification needs glycerol phosphate (Glyc3P) –WAT cannot make Glyc3P from glycerol –Instead Glyc3P is made by glycolysis As fatty acids stripped out, chylomicron becomes smaller –And more cholesterol rich NB. Cholesterol in lipoproteins mainly in the form of cholesterol esters –Form chylomicron remnants

4. Cholesterol Ester Cholesterol ester is totally hydrophobic

5. Liver: Import/Export Control Chylomicron remnants taken up by liver Endocytotic process Internal digestion of remnants Release of cholesterol into the liver Liver assembles VLDL from fat and cholesterol esters The fat could have been made by lipogenesis VLDL excreted into the blood stream

6. VLDL & LDL - Transport of Cholesterol LPL in peripheral tissues works on VLDL just as it did on chylomicrons VLDL becomes depleted in fat Remaining particle (LDL) relatively cholesterol rich Tissues take up LDL through LDL receptor Endocytotic process like chylomicron remnants. This is how cholesterol is delivered to the tissues

7. LDL & Cholesterol Tissues express LDL receptors ONLY if they want cholesterol Nearly all of our cells can produce cholesterol themselves –  when cells have enough cholesterol, they will stop making cholesterol & stop expressing LDL receptor Macrophages take up LDL without control, especially if LDL is oxidized  produce foam cells  form plaques HMG-CoA reductase is the rate limiting step in making cholesterol –Can be inhibited by statins

8. Reverse Cholesterol Transport

9. Ways to Reduce Blood Cholesterol Reduce consumption of cholesterol –Less meat, dairy products –But intake of cholesterol is very small vs stores  reabsorption of bile salts by using resins that bind to bile salts – liver has to make more bile salts from cholesterol Inhibit absorption of cholesterol from gut –Phytosterols as competitive inhibitors? Inhibit cholesterol synthesis by using “statins” which inhibit HMG-CoA reductase Consume polyunsaturated fatty acids – high saturated fat results in  HDL and  LDL

10. Cholesterol Flux Total cholesterol in body ~140g ~1g of cholesterol enters the body each day from diet –But only 0.5 g absorbed ~18g bile salts secreted into gut per day – and 17.5g is reabsorbed per day – the net loss of bile salt is very little (~0.5 g/day) So amount absorbed = amount lost as bile salts –A reduction in intake will most likely be met by an increase in endogeous choleseterol synthesis But compare the store size to the intake –140 g to 0.5 g –vs carbohydrate for which the store size and intake are similar magnitude –vs fat – intake (100 g) < store (15,000 g)

11. Importance of Cholesterol Cholesterol is important for: –Steroid hormone synthesis –Regulating membrane fluidity Membrane fluidity is important for: –Structural integrity –Receptor/enzyme activity

12. Membrane with Saturated FA saturated  FA –No double bond in FA Membrane crystalline

13. Membrane with Unsaturated FA Unsaturated FA  Kinks Membrane is less crystalline, more fluid and more permeable

14. Cholesterol & Membrane Fluidity Cholesterol “fine tunes” membrane fluidity