Lecture 14

Lipoprotein and Cholesterol Metabolism

Delivery of Fat to TissuesChylomicrons 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

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

Cholesterol Ester

• Cholesterol ester is totally hydrophobic

Liver: Import/Export ControlChylomicron 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

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

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

Reverse Cholesterol Transport

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

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)

Importance of Cholesterol

• Cholesterol is important for:– Steroid hormone synthesis– Regulating membrane fluidity

• Membrane fluidity is important for:– Structural integrity– Receptor/enzyme activity

Membrane with Saturated FA

• saturated FA – No double bond in FA

• Membrane crystalline

Membrane with Unsaturated FA

• Unsaturated FA Kinks• Membrane is less crystalline, more fluid and

more permeable

Cholesterol & Membrane Fluidity

• Cholesterol “fine tunes” membrane fluidity