56 - Cholesterol Synthesis and Lipoprotein Transport Flashcards
Chemical type of cholesterol
Sterol (modified steroid)
Function of cholesterol in cell membranes
Required for membrane permeability and fluidity
What is cholesterol an important component of?
1)
2)
3)
1) Bile acids
2) Steroid hormones
3) Vitamin D
Is a precursor to these
Critical intermediates in cholesterol synthesis pathway
1)
2)
3)
1) HMG-CoA (hydroxymethylglutaryl)
2) Isoprene
3) Squalene
Function of lipoproteins
Carry cholesterol in the blood
Statin mechanism
HMG-CoA reductase inhibitors
Above what level of total blood cholesterol does risk of heart disease significantly increase?
5mM
Is cholesterol found in plants?
No.
Fates of cholesterol synthesised in the liver 1) 2) 3) 4)
1) Transport (esterified, assembled into VLDL)
2) Bile acid synthesis (stored in gall bladder, used to emulsify dietary fats)
3) Vitamin D, steroid hormone synthesis (in gonads, adrenal glands, skin)
4) Membranes (10-50% of membrane lipid)
What does cholesterol do in a cell membrane?
1)
2)
3)
1) Provides adjustment to mammalian membrane fluidity at 37 degrees.
2) Rigid cholesterol ring fits in between unsaturated fatty acyl chains, makes membrane less fluid.
3) Membrane rafts have higher concentrations of cholesterol, glycolipids, sphingolipids.
Steps of cholesterol synthesis 1) 2) 3) 4) 5) 6) 7)
1) Acetyl-CoA generated in mitochondria
2) Acetyl-CoA converted to HMG-CoA
3) HMG-CoA converted to mevalonic acid by HMG-CoA reductase
4) Mevalonic acid converted to activated isoprene
5) Activated isoprene converted to squalene
6) Squalene converted to cholesterol
7) Cholesterol negatively feeds back on HMG-CoA reductase.
Effect of esterifying cholesterol
Makes it more hydrophobic. Easier to incorporate into lipoprotein structures
What is activated isoprene?
An intermediate in cholesterol synthesis.
Made from mevalonic acid.
Converted to squalene
Derivatives of activated isoprene
1)
2)
1) Carotenoids
2) Quinone electron carriers (EG: ubiquinone in e- transport chain)
Why is cholesterol transported in lipoproteins?
1)
2)
1) Hydrophobic.
2) Would alter properties of membranes and cause problems if delivered to wrong site
Chylomicron role
Package TAGs and esterified cholesterol from GIT
VLDL role
Package TAG and cholesterol esters stored and generated in the liver
Lipoprotein lipase
Enzyme on vascular wall that removes TAGs from LDL, VLDL.
TAGS enter muscle and adipocytes
LDL role
When VLDL is exposed to lipoprotein lipase, can either become IDL fragments or LDL, which delivers remaining cholesterol esters from VLDL to tissues
HDL role
Scavenges free cholesterol in blood, transports to liver for bile salt formation
Prevents macrophages from becoming foam cells
Where are chylomicrons formed?
Intestinal mucosa
Via which structures do chylomicrons transport TAGS?
Blood vessels and lymphatics
Apolipoproteins associated with chylomicrons
1)
2)
3)
1) ApoA-I to V
2) ApoB 48
3) ApoC-I to III
VLDL site of synthesis
Liver
Apolipoproteins associated with VLDL 1) 2) 3) 4)
1) ApoA-V (involved in uptake of LDL remnants)
2) ApoB-100
3) ApoC-I to III
4) ApoE
LDL precursor
VLDL
LDL role vs VLDL role
VLDL delivers TAGs to tissues.
LDL delivers cholesterol to tissues
Apolipoproteins associated with LDL
1)
2)
1) ApoA-V
2) ApoB-100
HDL site of synthesis
Liver and intestine
HDL synthesis
1)
2)
1) ApoA-I starts process of HDL synthesis
2) Two ApoA-I proteins make a hydrophobic ring that rounds up cholesterol esters and phospholipids. This forms mature HDL
Liver receptor that HDL binds to
SR-B1.
For transfer of cholesterol cargo to liver
Enzyme in liver that helps VLDL form
ACAT (acyl-CoA-cholesterol acyl transferase)
Enzyme in plasma that helps HDL scavenge cholesterol from membranes
LCAT (lecithin-cholesterol acyl transferase)
Examples of dyslipidaemias
1)
2)
3)
1) Hypercholesterolaemia
2) Hypertriglyceridaemia
3) Decrease in HDL cholesterol
Atherosclerosis formation 1) 2) 3) 4) 5) 6) 7)
1) Modified (oxidised) LDL accumulates in an artery wall (favoured by high LDL).
2) Endothelial cells in the artery react by displaying adhesion molecules.
3) White cells (monocytes and T-cells) invade the tissue and secrete inflammatory
mediators (cytokines).
4) Macrophages appear, take up the modified LDLs using scavenger receptors.
5) Macrophages become engorged with cholesterol. At this stage they are called
foam cells.
6) Fibrous tissue develops to trap the foam cells.
7) Foam cells produce “tissue factor” that can lead to a blood clot in the artery upon
rupture of the plaque.
Rate-limiting step in cholesterol synthesis
HMG-CoA reductase conversion of HMG-CoA to mevalonate
Drugs that are competitive inhibitors of HMG-CoA
Statins
Possible serious side effect of statin medication
Depletion of Q10. This is an electron carrier in mitochondrial e- transport chain.
This can have deleterious effects on cardiac and skeletal muscle.
