Lipid Synthesis, Fat Storage and Transport

Question 1

1) What is synthesised due to excess CHO?

Answer 1

Fat

Question 2

2) Which hormone stimulates fatty acid synthesis from Acetyl CoA?

Answer 2

Insulin (in the fed state)

Question 3

3) Describe how Acetyl CoA leaves the mitochondria

Answer 3

• Acetyl CoA must combine with oxaloacetate in order to leave the mitochondria, so forms citrate
• Citrate leaves the mitochondrion [is able to when concentration of citrate exceeds the oxidation capacity of the TCA cycle] into the cytosol and breaks back down into Acetyl CoA and oxaloacetate
• Acetyl CoA goes on to fat synthesis

Question 4

4) Describe the process of fatty acid synthesis

Answer 4

• Acetyl CoA –> Malonyl CoA
• catalysed by Acetyl CoA carboxylase
• addition of bicarbonate HCO3- (provides 1C, from CO2)
  ATP –> ADP + Pi

[The Rate Limiting Step]

Question 5

5) Describe the pattern in which the fatty acid chain grows in carbons

Answer 5

+3C : acetyl CoA (2C) and HCO3-
-1C : CO2 leaves

Overall: +2C at a time

Question 6

6) Which cofactor is involved in fatty acid synthesis (provides H)?

Answer 6

NADPH (from hexose monophosphate shunt, made in liver)

Question 7

7) Describe the enzyme fatty acid synthetase

Answer 7

Multiple active sites on the polypeptide chain
Hydrogenase and dehydrogenase reactions can occur
Long enzyme, only found in humans

Question 8

8) Which enzyme does the liver contain to allow the phosphorylation of glycerol phosphate in TAG synthesis?

Answer 8

Glycerol kinase

Question 9

9) Define and describe the lipoprotein structure

Answer 9

• Proteins that are insoluble in water and need to be transported as a lipid-protein complex
• Inner core of TAG and cholesterol esters
• Outer core is a single layer of phospholipids, with cholesterol and apoproteins embedded

[TAG binds to apoproteins and phospholipids forming a VLDL, in order to be able to circulate in the blood]

Question 10

10) Define apoproteins and state their function

Answer 10

• Proteins that have a structural role, they are recognised by cell membrane receptors and activate certain enzymes in lipid metabolism

Question 11

11) State the 4 classes of lipoproteins and the major lipid each one transports

Answer 11

• Chylomicrons: largest + lowest density, mainly carries dietary TAG (from the small intestine)

- Very Low Density Lipoproteins: Mainly carries 
endogenous TAG (not from diet, synthesised internally)

• Low Density Lipoproteins: Fat removed from VLDLs, mainly carries cholesterol to the tissues
• High Density Lipoproteins: Mainly carries cholesterol from tissues to liver

Question 12

12) Describe the transport of lipid from the gut (exogenous/dietary fat) via chylomicrons

Answer 12

• Newly formed chylomicrons (bound to Apoprotein B-48) in small intestine bind to 2 apoproteins from HDL, which are transported to the capillaries
• At the capillaries, Apoprotein C-II leaves and is recycled, back to HDL ,and some of the TAG is unloaded by lipase
  [this unloaded TAG enters the tissue, e.g. adipose, as fatty acids, then returns to its TAG form]
• Remaining TAG: some glycerol is formed and the rest (a chylomicron remnant) goes to the liver

Question 13

13) State the two apoproteins which bind to chylomicrons in order for transport to capillaries

Answer 13

• Apoprotein C-II (recycled back to HDL afterwards)

- Apoprotein E (remains bound to the chylomicron so liver can recognise the remnant and absorb it later)

Question 14

14) How does the liver recognise the chylomicron remnant?

Answer 14

Liver has an apoprotein E receptor on the surface which binds to the apoprotein E on the chylomicron remnant, allowing uptake

Question 15

15) Why is lipase situated outside the cell, rather than inside the cell?

Answer 15

TAG complex cannot enter the cell and needs to be broken down by the lipase first

Question 16

16) Describe the transport of lipid from the liver (endogenous fat) via VLDLs and LDLs

Answer 16

• VLDL leaves the liver -> this is TAG bound to ApoB-100 (apolipoprotein) and then 2 apoproteins (C-II and E from HDL) bind
• VLDL passes through capillary, lipase breaks down some TAG and this enters tissue as FA, some glycerol is formed and goes to the liver, the remaining complex is Intermediate Density Lipoprotein (IDL)
• Apoproteins C-II and E are recycled back to HDL, so LDL is formed (a portion of the fat originally from VLDL)
• Half LDL goes to liver and half to peripheral tissue, ApoB-100 binds to ApoB-100 receptors at both sites

Question 17

17) Describe how dietary cholesterol intake affects internal cholesterol synthesis

Answer 17

• Cholesterol is synthesised by every cell
• If cholesterol is consumed, there is a lower rate of cholesterol synthesis internally
• This is regulated in order to prevent a high concentration of LDL
• Cholesterol controls its own synthesis and the number of LDL receptors on the cell surface

Question 18

18) Describe the role of HDL in cholesterol transport

Answer 18

• HDL from liver and small intestine, already has apoA-1 bound to it
• Cholesterol is picked up from peripheral tissue, OH group must be neutralised by addition of fatty acid from lecithin, via lecithin cholesterol acyl transferase [LCAT] (activated by apoA-1)
• LPC and PC also bound to the new complex ‘Cholesterol Ester’ (HDL + Cholesterol + FA) which are the components of lecithin, minus the FA
• cholesterol ester returns to the liver

Question 19

19) Describe how cholesterol regulates its own receptor synthesis

Answer 19

• LDL particles reach cell, bind to receptors and enter via endocytosis
• (Receptors on surface of cell are recycled)
• Lysosomes break down outside of phospholipid vesicle, releasing cholesterol which affects nucleus
• Nucleus controls cholesterol receptor synthesis and HMG-CoA reductase production (enzyme involved in cholesterol synthesis)

Question 20

20) Outline the stages of cholesterol synthesis

Answer 20

Acetyl CoA --> HMG-CoA
- addition of acetoacetyl CoA
HMG-CoA --> mevalonate 
- enzyme HMG-CoA reductase [Rate Limiting Step]
Mevalonate --> Cholesterol

Question 21

21) State 2 functions of LDL receptors

Answer 21

• recognise ApoB-100 (receptors on liver and peripheral tissue, allowing LDL to bind)
• Remove LDL from circulation (receptor mediated endocytosis)

[Deficiency of LDL receptors = familial hypercholesterolaemia, risk of premature death]

Question 22

22) Indicate the importance of HMG-CoA reductase inhibitors in the treatment of hypercholesterolaemia

Answer 22

• HMG-CoA inhibitors inhibit the rate limiting step of cholesterol synthesis, therefore cholesterol is not synthesised
• prevents high concentrations of LDL building up and lower blood cholesterol levels

Question 23

23) Describe atherosclerosis

Answer 23

Plaque: complex structure involving inflammation and proliferation of smooth muscle in the artery wall

• contains connective tissue and cholesterol-rich lipid
• Starts as a fatty streak from accumulation of foam cells (macrophages filled with lipid, mainly cholesterol)
• scavenger receptors take up LDL without B-100 receptors, causing foam cell formation -> Myo.Infarction

Question 24

24) Give 4 examples of genetic hyperlipoproteinaemias and their consequences

Answer 24

• Defective LDL receptor: hypercholesterolaemia, high LDL in blood
• Lipoprotein lipase deficiency: high chlyomicrons and VLDL concentrations
• Deficiency of apoprotein C-II: high chylomicrons and VLDL conc
• Deficiency of apoproteins involved in remnant uptake (B-100, E): high chylomicron and VLDL remnant conc

Question 25

25) State 5 risk factors for secondary (non-hereditary) hyperlipoproteinaemias

Answer 25

• Alcoholism
• Obesity
• Type 2 diabetes
• Dietary cholesterol intake
• Dietary fatty acid intake (n-6 PUFA: lowers cholesterol while n-3: lowers TAG)