Lipid Metabolism

Question 1

What is the ratio of lipoproteins which is associated with atherosclerosis?

Answer 1

elevated LDL and decreased HDL

Question 2

How are non-polar lipids transported within the blood?

Answer 2

within lipoproteins either high density - HDL or low density - LDL

Question 3

What are apoproteins?

Answer 3

Specialised proteins within the outer monolayer of the hydrophilic coat
they are recognised by receptors in liver and other tissues allowing them to bind to cells

Question 4

What is a lipoprotein comprised of?

Answer 4

a hydrphobic core - containing esterified cholesterol and triacylglycerols
a hydophilic coat - compromising of a monolayer of amphipathic cholesterol, phospholipids and apoproteins

Question 5

What are the 4 main classes of lipoproteins?

Answer 5

HDL particles (contain apoA-I and apoA-II)
LDL particles (contain apoB-100)
Very-low density lipoprotein (VLDL) particles (contain apoB-100)
Chylomicrons (contain apoB-48)

Question 6

What is the function of ApoB-Containing Lipoproteins?

Answer 6

deliver TAGs to muscle for ATP biogenesis and adipocytes for storage

Question 7

Chylomicrons function

Answer 7

they are formed in the intestinal cells and transport dietary triglycerides - the exogenous pathway

Question 8

Very low density lipoproteins function

Answer 8

they are formed in liver cells and transport TAGs synthesised by that organ - the endogenous pathway

Question 9

The stages of the existence of ApoB-containing liposomes

Answer 9

Assembly - (apoB-100 in liver and apoB-48 in the intestine)
Intravascular metabolism (involving hydrolysis of the TAG core)
Receptor mediated clearance

Question 10

How are TAGs (triacylglycerols) formed?

Answer 10

the monoglycerides and free fatty acid from dietary fat diffuse into the enterocytes and are synthesised into TAGs

Question 11

What happens to cholesterol in the enterocytes?

Answer 11

It enters through the NPC1L1 and then undergoes esterification

Question 12

Where does cholesterol used in the body come from?

Answer 12

25% from diet

75% from bile

Question 13

Once assembled how does the chylomicron exit the enterocyte?

Answer 13

exocytosis

Question 14

What is the class of drugs best for reducing total and LDL cholesterol?

Answer 14

Statins e.g. sinvaststin and atrovastatin

Question 15

When are statins normally given?

Answer 15

At night because the majority of cholesterol seems to be made in the morning hence they are given before the peak

Question 16

What are the main adverse effects of statins?

Answer 16

muscle pain and rhabdomylosis (skeletal muscle breakdown) made worse when taken with fibrates

Question 17

What are fibrates used to treat?

Answer 17

they reduce TGA levels to be reduced

Question 18

Why do you not give fibrates to alcoholics?

Answer 18

they are more prone to muscle damage and breakdown therefore despite their high triglyceride levels these drugs are not recommended

Question 19

What is the role of chylomicrons and VLDL particles?

Answer 19

To target TAG delivery to adipose and muscle tissue - activated by transfer of apoC-II from HDL particles

Question 20

What is the intravascular metabolism of ApoB-containing lipoproteins?

Answer 20

ApoC-II facilitates chylomicron and VLDL particles binding to Lipoprotein lipase (LPL) - (lipolytic enzyme associated with the capillary endothelium)
LPL hydrolyses core TAGs to free fatty acids and glycerol which enter tissues

Question 21

What is a MTP?

Answer 21

a microsomal triglyceride transfer protein

Question 22

MTP lipidates apoB-100 form what?

Answer 22

nascent VLDL which coalesces with TAG droplets

Question 23

What is the process of clearing ApoB-containing lipoproteins?

Answer 23

1. LPL, due to TAG metabolism causes chylomicrons and VLDL particles to become enriched with cholestryl esters
2. chylomicrons and VLDL dissociate from LPL
3. ApoC-II is transferred back to HDL particles in exchange for apoE a high affinity ligand for receptor mediated clearance - particles are now remnants
4. The remnants are returned to the liver and metabolised by hepatic lipase
5. all chylomicron remnants and 50% of VLDL remnants are cleared by receptor-mediated endocytosis into hepatocytes
6. the remaining VLDL remnants lose further TAG through hepatic lipase and become smaller and enriched in cholesteryl ester and via intermediate density lipoproteins thry become LDL particles lacking apoE and solely retaining apoB-100

Question 24

How LDL particles are cleared?

Answer 24

• dependent on LDL receptor expressed by the liver and other tissues
• clearance by the liver is most important
• LDL uptake by particles occurs via receptor-mediated endocytosis
• in the cell at the lysosome cholesterol is released from cholesteryl ester via hydrolysis

Question 25

What does released cholesterol do?

Answer 25

inhibits HMG-CoA reductase which is the rate limiting enzyme in de novo cholesterol synthesis down regulates LDL receptor expression may be stored as cholesterol ester or used as a precursor for bile salt synthesis

Question 26

Why is LDL 'bad' cholesterol?

Answer 26

It is very involved in the disease progression of atherosclerosis 1. LDL is taken up from the blood into the intima of the artery and subsequently it's oxidised to atherogenic oxidised LDL (OXLDL) 2. Monocytes migrate across the endothelium into the intima where they become macrophages 3. OXLDL is taken up by the macrophages and converts them to cholesterol-laden foam cells which form a fatty streak 4. Release of inflammatory substances from various cell types causes division and proliferation of smooth muscle cells into the intima and the deposition of collagen 5. Atheromatous plaque forms consisting of a lipid core and a fibrous cap

Question 27

Why is HDL the 'good' cholesterol?

Answer 27

- Removes excess cholesterol from cells by transporting it in the plasma to the liver - HDL is mainly in the liver in its component parts - Mature HDL accepts excess cholesterol from plasma membrane of cells

Question 28

How do statins reduce total and LDL cholesterol?

Answer 28

- act as competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase - rate limiting step in cholesterol synthesis in hepatocytes - decrease in hepatocyte cholesterol synthesis means there is a compensatory increase in LDL receptor expression and enhanced clearance of LDL

Question 29

What effect do fibrates have on blood lipids?

Answer 29

- cause a pronounced decrease in TGAs and modestly decrease LDL and increase HDL - 1st line in patients with high TGA

Question 30

How do fibrates decrease TGA levels?

Answer 30

act as agonists of a nuclear receptor to enhance transcription of several genes including those which encode LPL

Question 31

Adverse effects of fibrates?

Answer 31

- myositis (rarely) shouldn't be used with statins - GI symptoms - Pruritus - rash

Question 32

How do bile acid binding resind (colestyramine, colestipol, colsevelam) reduce cholesterol?

Answer 32

- more bile salts are excreted so the cholestrol is converted to bile salts - oral and can have adverse effects on the GI tract - cause decreased absorption of TGAs and increased LDL receptor expression

Question 33

How does Ezetimibe reduce cholesterol?

Answer 33

to inhibit Niemann-Pick C1 like-1 (NPC1L1) transport protein in enterocytes of the duodenum, reducing the absorption of cholesterol

Question 34

How is ezetimibe used?

Answer 34

in combination with statins and causes LDL decrease | oral administration - half life 22 hours

Question 35

Adverse effects of ezetimibe

Answer 35

diarrhoea abdominal pain headache contraindicated in breastfeeding