Cholesterol Synthesis & Lipoprotein Transport

Question 1

What is the relationship between blood lipids and risk factors for heart disease?

Answer 1

• There is a positive correlation between blood LDL cholesterol levels and the risk of heart disease/MI.
• There is an inverse correlation between HDL cholesterol level and risk of heart disease
• A strong positive correlation exists between the ratio of total cholesterol/HDL cholesterol and the risk of heart disease (↑ratio, ↑risk)
• Risk increases significantly as total cholesterol levels rise above ~5mM

Question 2

What is cholesterol?

Answer 2

• 3-hydroxy-5,6-cholestene (C27)
• A precursor to steroid hormones, bile salts and vitamin-D
• A component of lipoproteins (chylomicrons, VLDL, LDL and HDL).
• Found in atherosclerotic plaque and gall stones.
• Not made in plants (plants have different sterols).

Question 3

Explain the steps involved in cholesterol synthesis.

Answer 3

Cholesterol made in liver has different fates:

1. Transport.
   - Fatty acid esterification of 3-OH group => uniformly fatty molecule. Assembled into VLDL (very low density lipoprotein) for transport to tissues.
2. Bile acids.
   - Stored in gallbladder.
   - Used on demand to emulsify fatty meals.
3. Steroid hormones & Vitamin D.
   - Synthesised from cholesterol in gonads/ adrenal glands & skin.
4. Membranes
   - Cholesterol (~10-50% of membrane lipid) provides fine adjustment to optimise mammalian membrane fluidity at 37◦C.
   - The rigid ring system of cholesterol fits into the kink of unsaturated fatty acyl chains to make the membrane less fluid.
   - Membrane rafts have higher levels of cholesterol, and glycolipids and sphingolipids (with saturated acyl chains)

Question 4

How is cholesterol actually transported in the body?

Answer 4

Cholesterol is not soluble in aqueous medium and would alter the properties of membranes and cause problems if they are delivered to the wrong site. So they are transported by encasing them in Lipoproteins.
=> Esterify the cholesterol to make it more hydrophobic
=> Incorporate the cholesterol ester into protein/ lipid composites, called lipoproteins

Question 5

Explain some principles of lipoprotein transport.

Answer 5

• Chylomicrons package triacyglycerol (TAG) and cholesterol-ester from the gut
• VLDL package triacyglycerol and cholesterol-ester stored/generated in the liver
• TAG is removed by the muscle & adipose tissue (by lipoprotein lipase)
• LDL carries remaining cholesterol-ester to tissues
• HDL is a scavenger and takes cholesterol to liver for bile salt formation.

Question 6

What are some features of Chylomicrons?

Answer 6

• Formed in the intestinal mucosa
• Carry TAGs from the diet to tissues via the lymphatics and blood
• Apolipoproteins: B-48; ApoE, Apo C-I to III (Apo C2), Apo A-I to V (involved in structure, and uptake of remnants)

Question 7

What are some features of Very Low Density Lipoproteins (VLDLs)?

Answer 7

• Formed in the liver
• Carry TAGs from the liver to tissues via the blood
• Apolipoproteins: Apo B-100; Apo E, Apo C-I to III, Apo A-V (involved in structure, and uptake of LDL remnants)

Question 8

What are some features of Low Density Lipoproteins (LDL)?

Answer 8

• Derived from VLDL
• Circulate to deliver cholesterol to tissues
• Apolipoproteins: Apo B100; Apo A-V (involved in structure and uptake)
• High circulating LDL => increased risk of heart disease

Question 9

What are some features of High Density Lipoprotein (HDL)?

Answer 9

• Made in liver and intestine
• Good cholesterol – involved in reverse cholesterol transport - Scavenges cholesterol from membranes and cells (converts it to cholesterol-ester for transport).
• Acts on macrophages to stop them becoming foam cells.
• Apo A-I starts the process of HDL formation.
• Two apo A-I proteins make a hydrophobic ring to round up cholesterol-ester and phospholipids to mature into HDL.
• Binds SR-B1 receptor in liver transfers its cargo of cholesterol-ester

Question 10

What are dyslipidaemias?

Answer 10

Disorders of Lipoprotein Metabolism

Question 11

Give some examples of dyslipidaemias?

Answer 11

• Hypercholesterolaemia:
  
  • ↑ total cholesterol (i.e. free and esterified) in blood (5.2 - 6.2 mM - borderline high; above 6.2mM - high)
• ↑ blood levels of cholesterol associated with LDL particles, including ↑ oxidised LDL particles (which are atherogenic
• Hypertriglyceridaemia:
  
  • ↑ blood levels of triglycerides, or ‘TGs’, also called ‘triacylglycerols’ abbreviated to ‘TAGs’
• ↓ HDL-cholesterol (i.e. free and esterified cholesterol associated with the HDL class of lipoproteins)

Question 12

What is atherosclerosis?

Answer 12

• Modified (oxidised) LDL accumulates in an artery wall (favoured by high LDL).
• Endothelial cells in the artery react by displaying adhesion molecules.
• White cells (monocytes and T-cells) invade the tissue and secrete inflammatory mediators (cytokines).
• Macrophages appear, take up the modified LDLs using scavenger receptors.
• Macrophages become engorged with cholesterol. At this stage they are called foam cells.
• Fibrous tissue develops to trap the foam cells.
• Foam cells produce tissue factor that can lead to a blood clot in the artery upon rupture of the plaque.
• Monocytes become macrophages and engulf modified LDL. Atherosclerotic plaque has a high amount of cholesterol.
• Foam cells enclosed in fibrous tissue = plaque
• Ruptured plaque exposes a coagulation factor (tissue factor) on foam cell membranes and cause blood clots.

Question 13

What is atherosclerosis?

Answer 13

• Modified (oxidised) LDL accumulates in an artery wall (favoured by high LDL).
• Endothelial cells in the artery react by displaying adhesion molecules.
• White cells (monocytes and T-cells) invade the tissue and secrete inflammatory mediators (cytokines).
• Macrophages appear, take up the modified LDLs using scavenger receptors.
• Macrophages become engorged with cholesterol. At this stage they are called foam cells.
• Fibrous tissue develops to trap the foam cells.
• Foam cells produce tissue factor that can lead to a blood clot in the artery upon rupture of the plaque.
• Monocytes become macrophages and engulf modified LDL. Atherosclerotic plaque has a high amount of cholesterol.
• Foam cells enclosed in fibrous tissue = plaque
• Ruptured plaque exposes a coagulation factor (tissue factor) on foam cell membranes and cause blood clots.

Question 14

How do you decrease cholesterol levels?

Answer 14

• Decreasing intake of cholesterol and triacylglycerols in food BUT
• HMG-CoA reductase is the rate limiting enzyme in cholesterol synthesis
• Drugs such as statins competitively inhibit HMG-CoA reductase

Question 15

Explain some mechanisms of statins.

Answer 15

• Statins are generally safe medications however since ubiquinone = Q= Q10= coenzyme Q and statin depletion of Q10 is linked to heart problems.
• Statins reduce Q10 production, which is involved in mitochondrial bioenergy transfer. The clinical use of HMG CoA-reductase inhibitors (statins) can cause skeletal and cardiac muscle complications.
• Supplements of Q10 do not appear to be effective in alleviating myotoxicity.
• Statins use 13 per cent of the money paid out by the Pharmaceutical Benefits Scheme (PBS).
• One in three Australians over the age of 50 now take them.
• There is concern that statins dispose to Type II diabetes and dementia