Lecture 3: Cholesterol Metabolism

Three important features of cholesterol structurally

Hydroxyl group on C-3, alkyl chain on C-17, and a 4 fused ring system

Overall step one of cholesterol metabolism

Formation of HMG - CoA which is identical to ketogenesis except the enzymes here are systolic instead of mitochondrial, the formation of mevalonate the rate limiting step of cholesterol synthesis

mechanism of step one

Acetyl-COA + Acetyl-CoA → Thiolase → Acetoacetyl-CoA +CoA-SH

Acetoacetyl-CoA + Acetyl-CoA → HMG-CoA Synthase → HMG-CoA

HMG-CoA + NADPH → HMG-CoA reductase → Mevalonate + NADP+ +CoA-SH

Step two of cholesterol synthesis

Mevalonate to activated isoprene, 6 carbons → 5 carbons, activated by pyrophosphate, requires three ATP

Step three of cholesterol synthesis

isoprene (5C) + isoprene (5C) → Geranyl pyrophosphate (10C)

Geranyl (10C) + isoprene (5C) → farnesyl pyrophosphate (15C)

farnesyl (15C) + farnesyl (15C) → squalene (30C)

Sep four cholesterol synthesis

Cyclization of squalene into cholesterol, introduction of hydroxyl group to C3, no more carbons are added

Regulation of cholesterol synthesis

Cholesterol synthesis is energy expensive so we only want to do it when we are in the well-fed state (insulin presence)

Insulin will activate…

PDE which inhibits PKA by degrading cAMP into AMP which thus does not allow the inhibition of HMG-CoA reductase therefore cholesterol is synthesized

Glucagon will activate…

PKA which inhibits HMG-CoA reductase and stops cholesterol synthesis

The accumulation of cholesterol will cause excess cholesterol to oxidize (oxysterol) which…

Also inhibits HMG-CoA reductase

What is the job of plasma lipoproteins

To provide a mode of transport for other hydrophobic lipids

What is a plasma lipoprotein

A large complex made of apoproteins and a single layer of lipid membrane

Chylomicrons

Transports dietary fats as TAGs has ApoCII which activates lipoprotein lipase for TAG hydrolysis and fatty acid uptake

Low density lipoproteins (LDL)

Considered “bad cholesterol” has a ApoB100, binds to LDL receptors for receptor mediated endocytosis to deliver cholesterol to cells

High density lipoproteins (HDL)

“Good cholesterol”, has ApoA-1, activates LCAT, esterifies cholesterol, drives reverse cholesterol transport, interacts with transporters to bring cholesterol from tissues back to the liver

The steps of lipid transport

1. Cholesterol and TAGs are synthesized in the liver and packaged into VLDL

2. VLDLs enter the blood circulation and mature, acquire ApoCII and becomes metabolically active

3. ApoCII activates lipoprotein lipase which removes TAGs as free fatty acids and shrinks VLDL → LDLs

4. LDL is cholesterol rich and delivers cholesterol to cells via Apo B100 binding to LDL receptors

5. HDLs also originates in the liver and removes excess cholesterol from the tissue and returns it back to liver

Receptor mediated endocytosis

1. LDL binds to its receptor via ApoB100

2. Ligand and receptor are both internalized via endocytosis

3. Cholesterol, TAGs, and membrane lipids are processed and the receptor is recycled back to the membrane (if receptors are defective internalization or recycling can be impaired cholesterol would remain in the blood causing high Hypercholesteremia, is genetic)

Dysregulation of cholesterol transport

Problem that occurs when cholesterol transport isn’t working, LDL accumulate in blood causes atherosclerosis (plaque buildup) which can lead to heart disease and myocardial infraction